Treatment of pain with topical diclofenac

ABSTRACT

The field involves compositions useful for pain relief, including diclofenac solution and gel formulations, in particular methods of use thereof, articles of manufacture and kits that provide novel preclinical, clinical and other information to users.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/660,865, filed Mar. 4, 2010, which application is acontinuation-in-part (CIP) of U.S. patent application Ser. No.12/459,998, filed Jul. 10, 2009, which in turn claims priority to U.S.Provisional Patent Application 61/211,600 filed Mar. 31, 2009, thedisclosures of which are herein incorporated by reference in theirentireties.

FIELD

The field involves the delivery of compounds useful for pain relief,including diclofenac formulations, methods of use thereof, articles ofmanufacture and kits that include providing novel preclinical, clinicaland other information to users.

BACKGROUND

The following includes information that may be useful in understandingthe present invention. It is not an admission that any of theinformation provided herein is prior art, or relevant, to the presentlydescribed or claimed inventions, or that any publication or documentthat is specifically or implicitly referenced is prior art.

Today, pain has become the universal disorder, a serious and costlypublic health issue, and a challenge for family, friends, and healthcare providers who must give support to the individual suffering fromthe physical as well as the emotional consequences of pain. In general,there are two basic types of pain, acute and chronic. Acute pain, forthe most part, results from disease, inflammation, or injury to tissues.This type of pain generally comes on suddenly, for example, after traumaor surgery. In some instances, it can become chronic. Chronic pain iswidely believed to represent disease itself. Chronic pain persists overa longer period of time than acute pain and is resistant to most medicaltreatments. It can, and often does, cause severe problems for patients.

Arthritis is considered to be one of the most pervasive diseases in theUnited States and a leading cause of disability. According to theCenters for Disease Control and Prevention, it is estimated that 1 ofevery 3 Americans is affected by one or more of the more than 100 typesof arthritis. Pain, particularly of the joints throughout the body,characterizes arthritis. Psoriasis, primarily a skin disorder, canprogress to psoriatic arthritis if left untreated. Rheumatoid arthritis,osteoarthritis, and ankylosing spondylitis are all examples ofdegenerative arthritic diseases.

In addition to, for example, arthritic causes, normal function of ajoint and its movement, and other portions of the body, can be severelyimpaired as a result of trauma or following orthopedic and othersurgical procedures. This may result in tenderness, aching, pain, andlengthy recovery times, as well as loss of joint mobility or reducedrange of motion, tonicity, or elasticity of the joint/articularstructures, such as for example, muscle, tendon, capsule, bone, orligament. Reduced joint mobility may also involve permanently altered orshortened joint or tissue architecture. Altered or abnormal jointmobility or joint architecture may also be associated with or caused bya variety of injuries and conditions such as, for example, metabolicdisorders, ischemia, injury to joint, capsule, bone, cartilage, tendon,ligament or muscle, fractures, subluxation, dislocation, crush injuries,prolonged immobilization (e.g., immobilization of a joint in a cast orsplint), and paralysis.

When non-pharmacological measures are not sufficient to control thesymptoms of osteoarthritis, current evidence-based guidelines supportpharmacological treatment with acetaminophen or oral nonsteroidalanti-inflammatory drugs (“NSAID”s) (American College of RheumatologySubcommittee on Osteoarthritis Guidelines. Recommendations for themedical management of osteoarthritis of the hip and knee: 2000 update.Arthritis Rheum. 2000; 43:1905-15; National Collaborating Centre forChronic Conditions. Osteoarthritis: National clinical guideline for careand management in adults. London: Royal College Physicians, 2008.Available at:http://www.nice.org.uk/nicemedia/pdf/CG059FullGuideline.pdf.; Zhang W,et al., Osteoarthritis Cartilage 2007; 15:981-1000; Zhang W, et al.,Osteoarthritis Cartilage 2008; 16:137-62. Acetaminophen has been linkedwith an increased risk of hepatic, hypertensive and cardiovascularadverse effects (e.g., Chan A T, et al., Circulation. 2006; 113:1578-87.Epub 2006 Mar. 13; Pincus T, et al., Ann Rheum Dis. 2004; 63:931-9).

NSAIDs are more effective (Towheed T E, J Rheumatol. 2006; 33:567-73)and carry more well-known gastrointestinal and cardiovascular risk(e.g., Antman E M, et al. Use of nonsteroidal anti-inflammatory drugs:an update for Clinicians: a scientific statement from the American HeartAssociation. Circulation. 2007; 115:1634-42; Chan A T, et al.Nonsteroidal anti-inflammatory drugs, acetaminophen, and the risk ofcardiovascular events. Circulation. 2006; 113:1578-87). The attempt tominimize the risk of both morbidity and potential mortality byprescribing COX-2 selective NSAIDs (‘coxitis’) has not achieved the goal(Kearney P M, et al. BMJ. 2006; 332:1302-8; Mamdani M, et al., BMJ.2004; 328:1415-6).

Diclofenac is used, most commonly, as the sodium or potassium salt forrelief from pain and inflammation such as musculoskeletal and jointdisorders including rheumatoid arthritis, osteoarthritis, and ankylosingspondylitis. U.S. Pat. Nos. 4,575,515 and 4,652,557 disclose topicalNSAID compositions, one of which, consisting of 1.5% diclofenac sodium,45.5% dimethylsulphoxide (“DMSO”), ethanol, propylene glycol, glycerine,and water, has been shown to be effective in the treatment of chronicosteoarthritis (e.g., Towheed, Journal of Rheumatology 33:3 567-573(2006); Oregon Evidence Based Practice Center entitled “ComparativeSafety and Effectiveness of Analgesics for Osteoarthritis,” AHRQ Pub.No. 06-EHC09-EF).

The skin provides a protective barrier against foreign materials andinfection. In mammals this barrier is created primarily by the outermostepidermal layer, the stratum corneum. The stratum corneum is comprisedof flat, extended, enucleated cells, termed corneocytes, the peripheryof which comprises a highly insoluble protein and lipid structure,called the cornified envelope (“CE”), surrounded by lipids. (Downing etal., Dermatology in General Medicine, Fitzpatrick, et al., eds., pp.210-221 (1993); Ponec, M, The Keratinocyte Handbook, Leigh, et al.,eds., pp. 351-363 (1994)). The CE is composed of polar lipids, such asceramides, sterols, and fatty acids, and a complicated network ofcross-linked proteins; however, the cytoplasm of stratum corneum cellsremains polar and aqueous. The stratum corneum is extremely thin (some20 microns) but provides a substantial barrier. Nevertheless, the skinhas been considered as a route for the administration of drugs. Varioustransdermal delivery systems achieve epidermal penetration by using askin penetration enhancing vehicle.

Topical NSAIDs present a safer potential alternative to oral therapy,with decreased systemic exposure to the active NSAID molecule. Whileprevious reviews (Mason L, et al., BMC Musculoskelet Disord. 2004; 5:28)have suggested that topical NSAIDs are effective for osteoarthritis, Linet al. (BMJ. 2004; 329:324-6) in their metaanalysis of the same studiesstressed that the various products showed symptom relief at 1 or 2 weeksbut loss of benefit at 4 weeks, and rejected them as there wasinsufficient evidence to justify a recommendation of long-term use.

Subsequently published randomized controlled studies have described apenetrating topical diclofenac solution in a dimethyl sulfoxide(DMSO)-containing vehicle as efficacious and safe in relieving thesymptoms of primary osteoarthritis of the knee over 4-, 6-, and 12-weektreatment periods (Baer P A, et al. BMC Musculoskelet Disord. 2005;6:44; Bookman A A, et al. CMAJ. 2004; 171:333-8; Roth S H, Shainhouse JZ. Arch Intern Med. 2004; 164:2017-23; Tugwell P S, et al. J Rheumatol.2004; 31:2002-12). Recent topical NSAID reviews and meta-analyses(Banning M., Br J Community Nurs 2006; 11:487-92; Banning M., ExpertOpin Pharmacother 2008; 9:2921-9; Biswal S, et al., J Rheumatol. 2006;33:1841-4; Haynes S, Gemmell H., Clinical Chiropractic 2007; 10:126-38;Moore R A, et al., Rheum Dis Clin N Am 2008; 34:415-32; Ozguney I,Expert Opin Pharmacother 2008; 9:1805-16; Towheed T E, J Rheumatol.2006; 33:567-73; Zacher J, et al., Current Medical Research and Opinions2008; 24(4):925-950) have evaluated the data from these topicaldiclofenac solution studies, and subsequently published nationalguidelines (Chou R, et al. Comparative Effectiveness and Safety ofAnalgesics for Osteoarthritis. Comparative Effectiveness Review No. 4.Rockville, Md.: Agency for Healthcare Research and Quality. September2006. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm;National Collaborating Centre for Chronic Conditions. Osteoarthritis:National clinical guideline for care and management in adults. London:Royal College Physicians, 2008. Available at:http://www.nice.org.uk/nicemedia/pdf/CG059FullGuideline.pdf; TannenbaumH, et al., J Rheumatol. 2006; 33:140-57; Zhang W, et al. 2007, supra;Zhang W, et al. 2008 supra) have cited these studies as evidence for theuse of topical NSAIDs as first line therapy for osteoarthritis. Topicaldiclofenac solution is used for the treatment of osteoarthritis and iscurrently approved for sale in Canada and several European countries.

The efficacy of topical NSAIDs, such as topical diclofenac solution, isthought to be due to local action of the active NSAID molecule followingits penetration through the skin to the tissue sites of inflammation andpain. Diclofenac sodium is a member of the arylacanoic acid group ofNSAIDs with lipophilic properties that limit its percutaneouspenetration (Nishihata T, et al., Chem. Pharm. Bull 1987; 35:3807-12).The biological property of DMSO to enhance skin penetration of bothhydrophilic and lipophilic molecules is known (Williams A C, Barry B W,Adv Drug Deliv Rev 2004; 56:603-18), with recent research focusing onthe mechanism of enhancement (Gurtovenko A A, Anwar J, J Phys Chem B2007; 111:10453-60). The percutaneous absorption of diclofenac followinga multidose regimen of a topical diclofenac solution (based on aDMSO-containing vehicle) was significantly enhanced compared to anaqueous diclofenac formulation without DMSO (Hewitt, P G, et al.,Pharmacol Res. 1998; 15:988-92). Within the extensive literature on DMSOare unsubstantiated claims of therapeutic efficacy in the treatment ofosteoarthritis, but no efficacy of DMSO vehicle was shown in a previous,4-week randomized controlled study of a topical diclofenac solution(Bookman A A, et al. Effect of a topical diclofenac solution forrelieving symptoms of primary osteoarthritis of the knee: a randomizedcontrolled trial. CMAJ. 2004; 171:333-8).

There remains a need in the art for methods of dosing topical diclofenacformulations, and providing users and prescribers with informationregarding drug product attributes and desired therapeutic effects aswell as instructions on uses in conjunction with other topical agents.Such needs are met by the inventions and discoveries provided herein.

BRIEF SUMMARY

The inventions described and claimed herein have many attributes andembodiments including, but not limited to, those set forth or describedor referenced in this Brief Summary. It is not intended to beall-inclusive and the inventions described and claimed herein are notlimited to or by the features or nonlimiting embodiments identified inthis Brief Summary, which is included for purposes of illustration onlyand not restriction.

Disclosed herein are methods of treatment and methods of manufacturingand using a topical diclofenac pharmaceutical product and relatedarticles and kits. Also disclosed herein are methods of preventing ortreating pain, including joint pain, and arthritis, includingosteoarthritis.

In one nonlimiting embodiment, a method of using topical diclofenac, andrelated methods of treatment, comprises informing a user of certaininformation regarding topical diclofenac, for example, a topicaldiclofenac solution comprising or consisting essentially of 1.5%diclofenac sodium (2-[(2,6-dichlorophenyl) amino] benzeneacetic acid,monosodium salt), 45.5% DMSO, ethanol, propylene glycol, glycerine, andwater (sometimes referred to herein as “Pennsaid”), said informationcomprising one or more of the following: (1) clinical effects of topicaldiclofenac dosing, including, for example, (a) the effects of particularfour times per day (“QID”) dosing; (b) the effects of QID dosing in oneor more clinical trials; (c) results from a 12-week, double-blindcontrolled trial of topical diclofenac in a solution containing dimethylsulfoxide in subjects with osteoarthritis of the knee which compared theperformance of said topical diclofenac solution against a vehiclesolution containing 45.5% dimethyl sulfoxide and a placebo solutioncontaining 2.3% dimethyl sulfoxide; (d) pharmacokinetic results from oneor more studies in which single and multiple doses of a topicaldiclofenac in a solution containing dimethyl sulfoxide was appliedtopically to healthy human volunteers; (2) an adverse event profile of atopical diclofenac, including, for example (a) that concomitant use oforal NSAIDs with topical diclofenac resulted in a higher rate of rectalhemorrhage, more frequent abnormal creatinine, urea and hemoglobin; (b)that in a controlled trial, a higher rate of contact dermatitis withvesicles was observed after treatment of 152 subjects with thecombination of topical diclofenac and oral diclofenac; (c) the resultsof a clinical study demonstrating that the addition of topicaldiclofenac to oral diclofenac did not cause an elevation of livertransaminases in osteoarthritis patients over use of oral diclofenacalone; (3) preclinical study results with topical diclofenac, including,for example, the results of an animal study in which no adverse oculareffects were observed after multiple-daily dermal application to ratsfor 26 weeks and minipigs for 52 weeks of DMSO at twice theconcentration found in a topical diclofenac solution (e.g., Pennsaid®);and (4) a statement that, once dry, sunscreen, insect repellant, lotion,moisturizer, cosmetics, and/or other topical products can be applied toan area previously treated with a topical diclofenac solution (e.g.,Pennsaid®).

In another nonlimiting embodiment, a method of using topical diclofenacfor the treatment of osteoarthritis, and related methods of treatment,comprises providing a patient with said topical diclofenac and providingcertain information to the patient regarding said topical diclofenac,for example, a topical diclofenac solution comprising or consistingessentially of 1.5% diclofenac sodium (2-[(2,6-dichlorophenyl) amino]benzeneacetic acid, monosodium salt), 45.5% DMSO, ethanol, propyleneglycol, glycerine, and water (sometimes referred to herein as“Pennsaid”), said information comprising one or more of the following:(1) clinical effects of topical diclofenac dosing, including, forexample, (a) the effects of particular four times per day (“QID”)dosing; (b) the effects of QID dosing in one or more clinical trials;(c) results from a 12-week, double-blind controlled trial of topicaldiclofenac in a solution containing dimethyl sulfoxide in subjects withosteoarthritis of the knee which compared the performance of saidtopical diclofenac solution against a vehicle solution containing 45.5%dimethyl sulfoxide and a placebo solution containing 2.3% dimethylsulfoxide; (d) pharmacokinetic results from one or more studies in whichsingle and multiple doses of a topical diclofenac in a solutioncontaining dimethyl sulfoxide was applied topically to healthy humanvolunteers; (2) an adverse event profile of a topical diclofenac,including, for example (a) that concomitant use of oral NSAIDs withtopical diclofenac resulted in a higher rate of rectal hemorrhage, morefrequent abnormal creatinine, urea and hemoglobin; (b) that in acontrolled trial, a higher rate of contact dermatitis with vesicles wasobserved after treatment of 152 subjects with the combination of topicaldiclofenac and oral diclofenac; (c) the results of a clinical studydemonstrating that the addition of topical diclofenac to oral diclofenacdid not cause an elevation of liver transaminases in osteoarthritispatients over use of oral diclofenac alone; (3) preclinical studyresults with topical diclofenac, including, for example, the results ofan animal study in which no adverse ocular effects were observed aftermultiple-daily dermal application to rats for 26 weeks and minipigs for52 weeks of DMSO at twice the concentration found in a topicaldiclofenac solution (e.g., Pennsaid®); and (4) a statement that, oncedry, sunscreen, insect repellant, lotion, moisturizer, cosmetics, and/orother topical products can be applied to an area previously treated witha topical diclofenac solution (e.g., Pennsaid®). In one nonlimitingembodiment the method is used to treat osteoarthritis in patients withosteoarthritis of the knee. In another non-limiting embodiment thepatient is further informed of the results of pharmacokinetic studies ofsaid topical diclofenac solution in healthy human volunteers in whichthe measured plasma half life of diclofenac following a single doseapplication was shorter than said the measured plasma half life ofdiclofenac following a multi-dose application.

In another nonlimiting embodiment, a method of using topical diclofenac,for example, a topical diclofenac solution comprising or consistingessentially of 1.5% diclofenac sodium, 45.5% DMSO, ethanol, propyleneglycol, glycerine, and water, and related methods of treatment,comprises obtaining topical diclofenac from a container providinginformation regarding (1) clinical effects of topical diclofenac dosing,including, for example, (a) the effects of particular QID dosing; (b)the effects of QID dosing in one or more clinical trials; (c) resultsfrom a 12-week, double-blind controlled trial of topical diclofenac in asolution containing dimethyl sulfoxide in subjects with osteoarthritisof the knee which compared the performance of said topical diclofenacsolution against a vehicle solution containing 45.5% dimethyl sulfoxideand a placebo solution containing 2.3% dimethyl sulfoxide; (d)pharmacokinetic results from one or more studies in which single andmultiple doses of a topical diclofenac in a solution containing dimethylsulfoxide was applied topically to healthy human volunteers; (2) anadverse event profile of topical diclofenac, including, for example (a)that concomitant use of oral NSAIDs with topical diclofenac resulted ina higher rate of rectal hemorrhage, more frequent abnormal creatinine,urea and hemoglobin; (b) that in a controlled trial, a higher rate ofcontact dermatitis with vesicles was observed after treatment of 152subjects with the combination of a topical diclofenac and oraldiclofenac; (c) the results of a clinical study demonstrating that theaddition of topical diclofenac to oral diclofenac did not cause anelevation of liver transaminases in osteoarthritis patients over use oforal diclofenac alone; (3) preclinical study results with topicaldiclofenac, including, for example, the results of an animal study inwhich no adverse ocular effects were observed after multiple-dailydermal application to rats for 26 weeks and minipigs for 52 weeks ofDMSO at twice the concentration found in a topical diclofenac solution(e.g., Pennsaid®); and (4) a statement that, once dry, sunscreen, insectrepellant, lotion, moisturizer, cosmetics, and/or other topical productscan be applied to an area previously treated with a topical diclofenacsolution (e.g., Pennsaid®).

In still yet another nonlimiting embodiment, a method of using topicaldiclofenac, for example, a topical diclofenac solution comprising orconsisting essentially of 1.5% diclofenac sodium, 45.5% DMSO, ethanol,propylene glycol, glycerine, and water, and related methods oftreatment, comprises providing a user with topical diclofenac, andinforming the user of one or more of the following: (1) clinical effectsof topical diclofenac dosing, including, for example, (a) the effects ofparticular QID dosing; (b) the effects of QID dosing in one or moreclinical trials; (c) results from a 12-week, double-blind controlledtrial of topical diclofenac in a solution containing dimethyl sulfoxidein subjects with osteoarthritis of the knee which compared theperformance of said topical diclofenac solution against a vehiclesolution containing 45.5% dimethyl sulfoxide and a placebo solutioncontaining 2.3% dimethyl sulfoxide; (d) pharmacokinetic results from oneor more studies in which single and multiple doses of a topicaldiclofenac in a solution containing dimethyl sulfoxide was appliedtopically to healthy human volunteers; (2) an adverse event profile of atopical diclofenac, including, for example (a) that concomitant use oforal NSAIDs with topical diclofenac resulted in a higher rate of rectalhemorrhage, more frequent abnormal creatinine, urea and hemoglobin; (b)that in a controlled trial, a higher rate of contact dermatitis withvesicles was observed after treatment of 152 subjects with thecombination of topical diclofenac and oral diclofenac; (c) the resultsof a clinical study demonstrating that the addition of topicaldiclofenac to oral diclofenac did not cause an elevation of livertransaminases in osteoarthritis patients over use of oral diclofenacalone; (3) preclinical study results with topical diclofenac, including,for example, the results of an animal study in which no adverse oculareffects were observed after multiple-daily dermal application to ratsfor 26 weeks and minipigs for 52 weeks of DMSO at twice theconcentration found in a topical diclofenac solution (e.g., Pennsaid®);and (4) a statement that, once dry, sunscreen, insect repellant, lotion,moisturizer, cosmetics, and/or other topical products can be applied toan area previously treated with a topical diclofenac solution (e.g.,Pennsaid®).

In another nonlimiting embodiment, a method of using topical diclofenac,for example, a topical diclofenac solution comprising or consistingessentially of 1.5% diclofenac sodium, 45.5% DMSO, ethanol, propyleneglycol, glycerine, and water, and related methods of treatment,comprises administering a topical diclofenac DMSO formulation to apatient, wherein the administration provides a therapeutic diclofenacconcentration by application (of, for example, about 40 drops) to one orboth knees to a subject having osteoarthritis of the knees, and the useris informed with regard to one or more of the following: (1) clinicaleffects of topical diclofenac in DMSO dosing, including, for example,(a) the effects of particular QID dosing; (b) the effects of QID dosingin one or more clinical trials; (c) results from a 12-week, double-blindcontrolled trial of topical diclofenac in a solution containing DMSO insubjects with osteoarthritis of the knee which compared the performanceof said topical diclofenac solution against a vehicle solutioncontaining 45.5% dimethyl sulfoxide and a placebo solution containing2.3% dimethyl sulfoxide; (d) pharmacokinetic results from one or morestudies in which single and multiple doses of a topical diclofenac in asolution containing dimethyl sulfoxide was applied topically to healthyhuman volunteers; (2) an adverse event profile of a topical diclofenacin DMSO, including, for example (a) that concomitant use of oral NSAIDswith topical diclofenac resulted in a higher rate of rectal hemorrhage,more frequent abnormal creatinine, urea and hemoglobin; (b) that in acontrolled trial, a higher rate of contact dermatitis with vesicles wasobserved after treatment of 152 subjects with the combination of topicaldiclofenac and oral diclofenac; (c) the results of a clinical studydemonstrating that the addition of topical diclofenac to oral diclofenacdid not cause an elevation of liver transaminases in osteoarthritispatients over use of oral diclofenac alone; (3) preclinical studyresults with topical diclofenac, including, for example, the results ofan animal study in which no adverse ocular effects were observed aftermultiple-daily dermal application to rats for 26 weeks and minipigs for52 weeks of DMSO at twice the concentration found in a topicaldiclofenac solution (e.g., Pennsaid®); and (4) a statement that, oncedry, sunscreen, insect repellant, lotion, moisturizer, cosmetics, and/orother topical products can be applied to an area previously treated witha topical diclofenac solution (e.g., Pennsaid®).

In yet another nonlimiting embodiment, a method of manufacturing atopical diclofenac pharmaceutical product comprises packaging a topicaldiclofenac dosage form, for example, a topical diclofenac solutioncomprising or consisting essentially of 1.5% diclofenac sodium(2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt),45.5% DMSO, ethanol, propylene glycol, glycerine, and water, with someor all of the following information, in written or electronic form: (1)clinical effects of topical diclofenac dosing, including, for example,(a) the effects of particular QID dosing; (b) the effects of QID dosingin one or more clinical trials; (c) results from a 12-week, double-blindcontrolled trial of topical diclofenac in a solution containing dimethylsulfoxide in subjects with osteoarthritis of the knee which compared theperformance of said topical diclofenac solution against a vehiclesolution containing 45.5% dimethyl sulfoxide and a placebo solutioncontaining 2.3% dimethyl sulfoxide; (d) pharmacokinetic results from oneor more studies in which single and multiple doses of a topicaldiclofenac in a vehicle solution containing dimethyl sulfoxide wasapplied topically to healthy human volunteers; (2) an adverse eventprofile of a topical diclofenac, including, for example (a) thatconcomitant use of oral NSAIDs with topical diclofenac resulted in ahigher rate of rectal hemorrhage, more frequent abnormal creatinine,urea and hemoglobin; (b) that in a controlled trial, a higher rate ofcontact dermatitis with vesicles was observed after treatment of 152subjects with the combination of topical diclofenac and oral diclofenac;(c) the results of a clinical study demonstrating that the addition oftopical diclofenac to oral diclofenac did not cause an elevation ofliver transaminases in osteoarthritis patients over use of oraldiclofenac alone; (3) preclinical study results with topical diclofenac,including, for example, the results of an animal study in which noadverse ocular effects were observed after multiple-daily dermalapplication to rats for 26 weeks and minipigs for 52 weeks of DMSO attwice the concentration found in a topical diclofenac solution (e.g.,Pennsaid®); and (4) a statement that, once dry, sunscreen, insectrepellant, lotion, moisturizer, cosmetics, and/or other topical productscan be applied to an area previously treated with a topical diclofenacsolution (e.g., Pennsaid®).

In one nonlimiting embodiment, an article of manufacture comprises acontainer containing a dosage form of topical diclofenac, for example, atopical diclofenac solution comprising or consisting essentially of 1.5%diclofenac sodium, 45.5% DMSO, ethanol, propylene glycol, glycerine, andwater, wherein the container is associated with published materialproviding some or all of the following information: (1) clinical effectsof topical diclofenac dosing, including, for example, (a) the effects ofparticular QID dosing; (b) the effects of QID dosing in one or moreclinical trials; (c) results from a 12-week, double-blind controlledtrial of topical diclofenac in a solution containing dimethyl sulfoxidein subjects with osteoarthritis of the knee which compared theperformance of said topical diclofenac solution against a vehiclesolution containing 45.5% dimethyl sulfoxide and a placebo solutioncontaining 2.3% dimethyl sulfoxide; (d) pharmacokinetic results from oneor more studies in which single and multiple doses of a topicaldiclofenac in a solution containing dimethyl sulfoxide was appliedtopically to healthy human volunteers; (2) an adverse event profile of atopical diclofenac, including, for example (a) that concomitant use oforal NSAIDs with topical diclofenac resulted in a higher rate of rectalhemorrhage, more frequent abnormal creatinine, urea and hemoglobin; (b)that in a controlled trial, a higher rate of contact dermatitis withvesicles was observed after treatment of 152 subjects with thecombination of topical diclofenac and oral diclofenac; (c) the resultsof a clinical study demonstrating that the addition of topicaldiclofenac to oral diclofenac did not cause an elevation of livertransaminases in osteoarthritis patients over use of oral diclofenacalone; (3) preclinical study results with topical diclofenac, including,for example, the results of an animal study in which no adverse oculareffects were observed after multiple-daily dermal application to ratsfor 26 weeks and minipigs for 52 weeks of DMSO at twice theconcentration found in a topical diclofenac solution (e.g., Pennsaid®);and (4) a statement that, once dry sunscreen, insect repellant, lotion,moisturizer, cosmetics, and/or other topical products can be applied toan area previously treated with a topical diclofenac solution (e.g.,Pennsaid®).

In one nonlimiting embodiment, information regarding the clinicaleffects of dosing of a topical diclofenac solution includes the effectsof 40-drop QID dosing of said topical diclofenac solution, and/or theeffects of 40-drop QID dosing of said topical diclofenac solution in oneor more clinical trials.

In one nonlimiting embodiment, the article of manufacture is a kit.Thus, one aspect of the invention provides a novel kit of partscomprising topical diclofenac (for example, a topical diclofenacsolution or gel as described, or referenced, herein) and informationinforming a user or prescriber of novel results from preclinical andclinical studies.

In one nonlimiting embodiment, or in any of the methods describedherein, the user or prescriber is informed of the results of or morepreclinical studies in which concomitant use of topical diclofenac withother topical products, including DEET (active ingredient in insectrepellent), 2,4-D (active ingredient in commonly used pesticides) andoxybenzone (active ingredient in sunscreens), was investigated. In oneaspect of this embodiment, the user or prescriber is informed thatrepeated application of topical diclofenac did not enhance the systemicabsorption of these products. In another aspect of this embodiment, theuser or prescriber is informed that before applying sunscreen, insectrepellant, lotion, moisturizer, cosmetics, or other topical medicationto the same skin surface of the knee treated with topical diclofenac,one should wait until the treated area is dry, which occurs most oftenwithin from about 10-15 or about 30 minutes. In another aspect of thisembodiment, including in any of the methods described herein, the useror prescriber is informed that concomitant use of topical diclofenac andsunscreens and insect repellants is safe. In another aspect of thisembodiment, including in any of the methods described herein, the useror prescriber is informed that use of topical diclofenac does not reducethe efficacy of a sunscreen. In another aspect of this embodiment,including in any of the methods described herein, the user or prescriberis informed that use of topical diclofenac does not reduce the efficacyof an insect repellant.

In one nonlimiting embodiment, or any of the methods described herein, auser may also be informed of the effects of use of other topicalproducts in conjunction with topical diclofenac in DMSO, including, forexample, that concomitant topical use of diclofenac in DMSO by repeatedapplication with other topical products, including DEET, 2,4-D and/oroxybenzone (active ingredient in sunscreens) did not enhance thesystemic absorption of these products; and/or (b) the effect of the useof topical diclofenac in DMSO on absorption of environmental toxins,including, for example, the results of a study showing that repeatedtopical application of diclofenac in DMSO did not increase systemicenvironmental toxin exposure.

In one nonlimiting embodiment, or in any of the methods describedherein, the user or prescriber is informed of the results of atransepidermal water loss study in which no alteration in skin barrierfunction following chronic use of topical diclofenac was found. In oneaspect of this embodiment, including in any of the methods describedherein, the user or prescriber is informed that the study was performedon human volunteers' skin.

In one nonlimiting embodiment, or in any of the methods describedherein, the user or prescriber is informed of the pharmacokineticresults from studies in which single and multiple doses of a topicaldiclofenac in a vehicle solution containing dimethyl sulfoxide wasapplied topically to healthy human volunteers;

In one nonlimiting embodiment, or in any of the methods describedherein, the user or prescriber is informed that in clinical trials thecombination of topical diclofenac and oral diclofenac, compared to oraldiclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs.less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea(20% vs. 12%), and hemoglobin (13% vs. 9%), but no difference inelevation of liver transaminases.

In one nonlimiting embodiment, or in any of the methods describedherein, the user or prescriber is informed that the diclofenac half lifeand elimination constant K_(el) for a topical diclofenac solutioncomprising or consisting essentially of 1.5% diclofenac sodium, 45.5%DMSO, ethanol, propylene glycol, glycerine, and water is statisticallysignificantly different depending on whether the solution is applied asa single dose or as multiple doses.

In one nonlimiting embodiment, the user or prescriber is informed of theresults of a clinical study demonstrating that the addition of topicaldiclofenac to oral diclofenac did not increase the incidence of certainsystemic adverse events in osteoarthritis patients. In one aspect ofthis embodiment, the user or prescriber is further informed that thecombination of topical diclofenac and oral diclofenac did not increasethe incidence of digestive system events over oral diclofenac alone. Inanother nonlimiting embodiment, the user or prescriber is informed of astudy showing that administration of topical diclofenac results in lessfrequent adverse events associated with the NSAID class than oraldiclofenac alone and/or the results of a clinical study demonstratingthat the addition of topical diclofenac to oral diclofenac did not causean elevation of liver transaminases in osteoarthritis patients over useof oral diclofenac alone.

In another nonlimiting embodiment, the user or prescriber is informed ofthe results of a clinical trial in which one knee was successfullytreated with topical diclofenac even though most subjects had bilateralosteoarthritis of the knees. In one aspect of this embodiment, the useror prescriber is further informed that topical diclofenac may be appliedto only one knee despite the existence of bilateral osteoarthritis.

In another nonlimiting embodiment, the user or prescriber is informedthat a regimen of topical diclofenac and oral diclofenac is useful fortreating an individual with persistent or breakthrough knee pain despiteusing an oral NSAID.

In another nonlimiting embodiment, the user or prescriber is informedthat topical diclofenac, or a regimen of topical diclofenac and oraldiclofenac, is useful when topical diclofenac is applied to only oneknee of a subject with osteoarthritis even though both knees of anindividual may be affected.

In yet another nonlimiting embodiment, the user is provided with some orall of the topical diclofenac clinical and preclinical informationdescribed herein for purposes of enhancing the safety profile of topicaldiclofenac.

The topical diclofenac composition will comprise diclofenac and at leastone transdermal penetration enhancer in an amount sufficient to aid inthe delivery of a therapeutically effective amount of diclofenac to adesired area. The topical diclofenac may also include one or morepharmaceutically acceptable carriers, thickening agents, solubilizingagents, dispersants, etc.

In certain embodiments, the diclofenac is in the form of apharmaceutically acceptable salt or free acid. Examples ofpharmaceutically acceptable salts include metal salts, including alkalimetal, alkaline earth metal, and nitrogen-based salts such as ammoniumsalts. Sodium, potassium, epolamine and diethylamine salts arepreferred. In one preferred embodiment the diclofenac is diclofenacmonosodium salt.

In one nonlimiting embodiment, the topical diclofenac is a solution.

In another nonlimiting embodiment, the topical diclofenac is a gel.

In one nonlimiting embodiment, the topical diclofenac is a solution thatcomprises or consists essentially of diclofenac and between about 40%and about 85% DMSO by weight of the solution, preferably between about40% and about 60% DMSO by weight of the solution, more preferablybetween about 40% and about 50% DMSO by weight of the solution, stillmore preferably between about 42.5% and about 48.5% DMSO by weight ofthe solution, and most preferably about 45.5% DMSO by weight of thesolution; a polyalcohol, preferably having 3-5 carbon atoms, for theretention of moisture in the skin, which in certain embodiments isglycerol or glycerine; a dispersant for assisting to disperse thecomponents in solution to provide a homogeneous solution when applied tothe skin and when penetrating the skin, which in one embodiment ispropylene glycol; and water.

In one nonlimiting embodiment, the topical diclofenac is a solutioncomprising or consisting essentially of 1.5% w/w diclofenac sodium(2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt) and45.5% w/w dimethyl sulfoxide.

In another nonlimiting embodiment, the topical diclofenac is a solutionthat comprises or consists essentially of 1.5% diclofenac sodium(2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt),45.5% DMSO, ethanol, propylene glycol, glycerine, and water.

In another nonlimiting embodiment, the topical diclofenac is a gelformulation according to PCT/US2007/081674 (International PublicationNo. WO 2008/049020 A2), the contents of which are incorporated herein intheir entirety by this reference. The topical diclofenac may be any ofthe formulations described or claimed therein. In another nonlimitingembodiment, the topical diclofenac is a gel formulation according to USPatent Application No. 20080300311 (published Dec. 4, 2008), thecontents of which are incorporated herein in their entirety by thisreference. The topical diclofenac may be any of the formulationsdescribed or claimed therein.

In another nonlimiting embodiment, the topical diclofenac is a gelformulation comprising diclofenac (e.g., diclofenac sodium), dimethylsulfoxide, ethanol, propylene glycol, one or more thickening agents, andwater. In one aspect of this embodiment, the topical diclofenac gelformulation further comprises glycerol. In another aspect, thethickening agent is selected from the group consisting of cellulosepolymers, carbomer polymers, a carbomer derivative, a cellulosederivative, polyvinyl alcohol, poloxamers, polysaccharides, and mixturesthereof.

In another nonlimiting embodiment, the topical diclofenac is a gelformulation comprising or consisting essentially of 1-5% w/w diclofenac(preferably diclofenac monosodium); 30-60% w/w dimethyl sulfoxide; 1-50%w/w ethanol; 1-15% w/w propylene glycol; a thickener; and water (addedto make 100% w/w). In a preferred aspect of this embodiment, the gelformulation has a viscosity of 10-50,000 centipoise.

In another nonlimiting embodiment, the topical diclofenac is a gelformulation comprising or consisting essentially of about 2% w/wdiclofenac (preferably diclofenac monosodium); about 45.5% w/w dimethylsulfoxide; about 23-29% w/w ethanol; about 11% w/w propylene glycol;about 0-6% w/w hydroxypropylcellulose (HY119); and water (added to make100% w/w). In a preferred aspect of this embodiment, the gel formulationhas a viscosity of 500-5,000 centipoise.

In another nonlimiting embodiment, the topical diclofenac is a gelformulation comprising or consisting essentially of diclofenac(preferably diclofenac monosodium) at a concentration selected from thegroup consisting of 1, 1.5, 2 and 3% w/w; dimethyl sulfoxide at aconcentration selected from the group consisting of 42, 43, 44, 45, 45.546, 47, 48 and 49% w/w and fractions in between; ethanol at 23-29% w/w;propylene glycol at a concentration selected from the group consistingof 9, 10, 11, 12, 13% w/w and fractions in between;hydroxypropylcellulose (HY119) at 0-6% w/w; and water (included in anamount sufficient to make 100% w/w). In a preferred aspect of thisembodiment, the gel formulation has a viscosity of about 500-5000centipoise.

In certain embodiments, the above-described topical diclofenac gelformulations include 1-5% glycerol. In such embodiments, the gelformulation will have a drying rate and a transdermal flux that aregreater than a comparative liquid topical diclofenac formulation. Inother embodiments, the above-described topical diclofenac gelformulations will have a pH of about 6.0 to about 10.0.

In another nonlimiting embodiment, the topical diclofenac is a gelformulation comprising diclofenac (e.g., diclofenac sodium), ethanol,dimethyl sulfoxide, propylene glycol, hydroxypropylcellulose and water.In one aspect of this embodiment, the hydroxypropylcellulose issubstituted with alklycellulose, hydroxyalkylcellulose,carboxyalkylcellulose, or sodium carboxyalklycellulose, where alkyl ismethyl, ethyl or propyl, or a mixture thereof.

In another aspect of the present invention, some or all of the userinformation described herein is provided and pain is reduced in asupporting body structure of a subject, including joints, muscles,tendons, ligaments, cartilage and skin, by topically administering to asubject in need thereof a pharmaceutical composition comprising atherapeutically effective amount of diclofenac in dimethyl sulfoxide,preferably 45.5% w/w dimethyl sulfoxide, or a pharmaceutical compositioncomprising a therapeutically effective amount of diclofenac in a gelformulation, as described herein, in PCT/US2007/081674, or in US PatentApplication No. 20080300311. In another nonlimiting embodiment, pain inthe musculoskeletal system of a subject is reduced. In anothernonlimiting embodiment, pain in a supporting body structure of a subjectand/or in the musculoskeletal system of a subject is reduced.

Various uses of the information provided herein following new clinicaland preclinical studies include uses for treatment, or in themanufacture or preparation of formulations, compositions, articles ofmanufacture and kits.

The invention also includes methods employing topical diclofenac, kitsand articles of manufacture useful for pain relief or prevention in thetreatment of a subject, including in the treatment of a subjectfollowing an invasive medical procedure or surgery, including anorthopedic procedure or surgery, or a subject predisposed to orotherwise at risk for pain, wherein said methods, kits and articles ofmanufacture comprise some or all of the user information describedherein. The topical diclofenac described herein is administered to asite of pain (acute or chronic, for example) and/or proximally thereto(including, for example, areas of reflected or secondary pain). Thus,for example, some or all of the user information described herein isprovided and the topical diclofenac is administered to the skin at asite of pain and/or to skin locations proximal thereto in a supportingbody structure of a subject, including joints, muscles, tendons,ligaments, cartilage and skin (including any one or more of these,together, or in any combination), and/or in the musculoskeletal system,by topical administration as provided herein, whereby pain is reduced.

In one aspect, the present invention is directed to a method forreducing pain in a supporting body structure of a subject, comprisingtopically administering to said subject in need thereof a pharmaceuticalcomposition comprising a therapeutically effective amount of atransdermal diclofenac solution or gel formulation comprising DMSO,whereby pain is reduced, and providing to a user some or all of theclinical and preclinical information described herein. According to onenonlimiting embodiment, the supporting body structure is a joint.According to another nonlimiting embodiment, the supporting bodystructure is selected from the group consisting of muscles, bones,tendons, ligaments and cartilage. These methods are suitable fortreating a subject suffering from arthritis. Conditions which may betreated include osteoarthritis, rheumatoid arthritis, and anklyosingspondylitis.

In a further nonlimiting embodiment this method is suitable for treatinga subject suffering from acute pain. Suitable pain conditions fortreatment by this method include back pain, knee pain, hip pain,shoulder pain, ankle or leg pain, hand pain or finger pain, in which auser is also provided with some or all of the clinical and preclinicalinformation described herein. In an alternate nonlimiting embodiment,the subject is suffering from chronic pain, which may include back pain,knee pain, hip pain, shoulder pain, ankle or leg pain, hand pain orfinger pain. In another nonlimiting embodiment, the subject is sufferingfrom postoperative pain.

In another aspect, the present invention is directed to a method forapplying multiple topical agents to an subject with pain comprisingtopically administering a pharmaceutical composition comprising atherapeutically effective amount of a topical diclofenac comprisingdiclofenac in DMSO, waiting for the treated area to dry (the time forwhich can be dependent on individual skin characteristics, environmentalconditions such as temperature and humidity, and surface area, beingoften about 5-30 minutes, or about 5-20 minutes, for example, ortypically about 10 minutes or less for a topical diclofenac preparation,including a topical diclofenac solution as described in the Examples),and applying another topical agent(s). In one nonlimiting embodiment,the subject has osteoarthritis. In another nonlimiting embodiment, thesubject has osteoarthritis of the knee. In one embodiment, the topicalagent administered after the topical diclofenac is a sunscreen or aninsect repellant.

In another nonlimiting embodiment, the invention includes a method ofprotecting a subject with osteoarthritis from UV exposure andalleviating the signs and symptoms of osteoarthritis in the subjectcomprising the steps of applying a therapeutically effective amount of atransdermal diclofenac solution or gel formulation comprising diclofenacin DMSO; waiting for the treated area to dry (the time for which can bedependent on individual skin characteristics, environmental conditionssuch as temperature and humidity, and surface area, being often about5-30 minutes, or about 5-20 minutes, for example, or typically about 10minutes or less for a topical diclofenac preparation, including atopical diclofenac solution as described in the Examples), and applyingsunscreen to all or a portion of the same area of treatment.

In a further aspect, provided is an article of manufacture comprising atopical diclofenac preparation (e.g., a solution or gel formulation fortransdermal administration as described herein) and a packagingmaterial, wherein said topical diclofenac preparation comprises a painrelief effective amount of diclofenac in DMSO, wherein said packagingmaterial comprises a label or insert that indicates that saidcomposition may be used for reducing pain in a supporting structure, andwherein a user is also provided with some or all of the clinical andpreclinical information described herein.

In another aspect, a kit of information concerning a topical diclofenacproduct comprising diclofenac and dimethyl sulfoxide is provided, saidkit comprising information about (a) clinical effects of dosing of atopical diclofenac solution comprising 1.5% w/w diclofenac sodium and45.5% w/w dimethyl sulfoxide, including (i) the effects of (for example,40-drop) QID dosing of said topical diclofenac solution; (ii) theeffects of (for example, 40-drop) QID dosing of said topical diclofenacsolution in one or more clinical trials; (iii) results from a 12-week,double-blind, controlled trial of said topical diclofenac solution insubjects with osteoarthritis of the knee which compared the performanceof said topical diclofenac solution against a vehicle solutioncontaining 45.5% dimethyl sulfoxide and a placebo solution containing2.3% dimethyl sulfoxide; and (iv) pharmacokinetic results from one ormore studies in which single and multiple doses of a topical diclofenacin a solution containing dimethyl sulfoxide was applied topically tohealthy human volunteers; (b) an adverse event profile for a topicaldiclofenac solution comprising 1.5% w/w diclofenac sodium and 45.5% w/wdimethyl sulfoxide, including, (i) concomitant use of oral NSAIDs withtopical diclofenac resulted in a higher rate of rectal hemorrhage, morefrequent abnormal creatinine, urea and hemoglobin; (ii) that in acontrolled trial, a higher rate of contact dermatitis with vesicles wasobserved after treatment of 152 subjects with the combination of topicaldiclofenac and oral diclofenac; and (iii) results of a clinical studydemonstrating that the addition of said topical diclofenac solution tooral diclofenac did not cause an elevation of liver transaminases overuse of oral diclofenac alone; (c) preclinical study results for atopical formulation comprising dimethyl sulfoxide, including forexample, the results of an animal study in which no adverse oculareffects were observed after multiple-daily dermal application to ratsfor 26 weeks and minipigs for 52 weeks of DMSO at twice theconcentration found in a topical diclofenac solution (e.g., Pennsaid®);and (d) a statement that, once dry, sunscreen, insect repellant, lotion,moisturizer, cosmetics, and/or other topical products can be applied toan area previously treated with a topical diclofenac solution (e.g.,Pennsaid®).

In another aspect, a method of treating osteoarthritis of the knee isprovided which comprises supplying a topical diclofenac preparation andthe Attachment to the patient.

Also provided is a method of obtaining marketing authorization from aregulatory authority for a topical diclofenac product comprisingreferencing the kit of information.

In another embodiment, a method for distribution of a topical diclofenacproduct is provided, comprising the steps of (a) obtaining marketingauthorization from a regulatory authority for a topical diclofenacproduct comprising referencing the kit of information; and providingsaid topical diclofenac product to one or more distributors.

These and other aspects of the present inventions, which are not limitedto or by the information in this Brief Summary, are provided below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows mean TEWL scores for Retin-A® by Day—ITT.

FIG. 2 shows mean TEWL Scores for Pennsaid® by Day—ITT.

FIG. 3 shows mean plasma concentration-time profile for diclofenacsodium (ng/mL).

FIG. 4 shows mean plasma concentration-time profile for dimethylsulfoxide (μg/mL).

FIG. 5 shows mean plasma concentration-time profile for diclofenacsodium (ng/mL).

FIG. 6 shows mean plasma concentration-time profile for dimethylsulfoxide (μg/mL).

FIG. 7 shows mean plasma concentration-time profile for dimethyl sulfone(μg/mL).

FIG. 8 shows log diclofenac plasma concentration versus time aftersingle and multiple dose application of a topical solution containing1.5% w/w diclofenac sodium and 45.5% DMSO.

FIG. 9 shows an analysis of elimination rate constant (K_(el)) aftersingle and multi dose application of a topical solution containing 1.5%w/w diclofenac sodium and 45.5% DMSO.

FIG. 10A shows diagram of FIG. 1. Dispense 10 drops of PENNSAID® at atime.

FIG. 10B shows diagram of FIG. 2. Spread PENNSAID® evenly on the front,and sides of your knee.

FIG. 10C shows diagram of FIG. 3. Spread PENNSAID® evenly on the back ofyour knee.

DETAILED DESCRIPTION

As used herein, a “disorder” is any disorder, disease, or conditioninvolving pain that would benefit from topical diclofenac.

“Enhancing the safety profile” of topical diclofenac means implementingactions or articles designed or intended to help reduce the incidence ofadverse events associated with administration of topical diclofenac,including adverse effects associated with patient-related factors (e.g.,age, gender, ethnicity, race, target illness, abnormalities ofcardiovascular, gastrointestinal, renal or hepatic function, co-morbidillnesses, characteristics such as pregnancy or environment, includingsun exposure) and topical diclofenac-related factors (e.g., dose, plasmalevel, duration of exposure, or concomitant medication).

“Informing” means referring to or providing, published materialincluding in electronic form, for example, providing published materialto a user; or presenting information orally, for example, bypresentation at a seminar, conference, or other educationalpresentation, by conversation between a pharmaceutical salesrepresentative and a medical care worker, or by conversation between amedical care worker and a patient; or demonstrating the intendedinformation to a user for the purpose of comprehension. “Published”material may be in any form, including printed and electronic forms.Electronic forms include material stored in any memory or data storageformat or medium (e.g., memory stick, CD, DVD, or other machine readableform), as well as materials available or accessible via the Internet oronline databases, for example.

A “medical care worker” means a worker in the health care field who mayneed or utilize information regarding topical diclofenac including adosage form thereof, including information on safety, efficacy, dosing,administration, or pharmacokinetics. Examples of medical workers includephysicians, pharmacists, physician's assistants, nurses, aides,caretakers (which can include family members or guardians), emergencymedical workers, and veterinarians.

As used herein, “musculoskeletal system” (also known as the locomotorsystem) refers to the system that gives animals the ability tophysically move using the muscles and the skeletal system. Themusculoskeletal system includes the skeleton, made by bones attached toother bones with joints and ligaments, and skeletal muscle attached tothe skeleton by tendons. Particularly useful applications of the presentinvention include the prevention or treatment of musculoskeletal pain,including pain that affects the joints, muscles, ligaments and tendons,along with bones.

As used herein, “pain” includes acute pain and chronic pain.

A “patient” means a subject in need of medical treatment. Medicaltreatment can include treatment of an existing condition, such as adisease or disorder, prophylactic or preventative treatment. In someembodiments the patient is a human patient.

A “pharmaceutical supplier” means a person (other than a medical careworker), business, charitable organization, governmental organization,or other entity involved in the transfer of topical diclofenac,including a dosage form thereof, between entities, for profit or not.Examples of pharmaceutical suppliers include pharmaceuticaldistributors, pharmacy chains, pharmacies (online or physical),hospitals, HMOs, supermarkets, the Veterans Administration, or foreignbusinesses or individuals importing topical diclofenac into the UnitedStates.

As used herein, “preventing” or “prevention” means preventing in wholeor in part, or ameliorating, reducing or controlling.

A “product” or “pharmaceutical product” means a dosage form of topicaldiclofenac plus published material and optionally packaging.

“Providing” means giving, administering, selling, distributing,transferring (for profit or not), manufacturing, compounding, ordispensing.

“Published material” means a medium providing information, includingprinted, audio, visual, or electronic medium, for example a flyer, anadvertisement, a product insert, printed labeling, an internet web site,an internet web page, an internet pop-up window, a radio or televisionbroadcast, a compact disk, a DVD, a podcast, an audio recording, orother recording or electronic medium.

“Safety” means the incidence or severity of adverse events associatedwith administration of topical diclofenac, including adverse effectsassociated with patient-related factors, including as noted above, andtopical diclofenac-related factors, including as noted above.

As used herein, “subject” refers to any mammal, including humans,domestic and farm animals, and zoo, sports, or pet animals, such asdogs, horses, cats, sheep, pigs, cows, etc. Non-limiting preferredmammals are a human, including adults, children, and the elderly.Non-limiting preferred sports animals are horses and dogs. Non-limitingpreferred pet animals are dogs and cats.

As used herein, “supporting body structure of a subject” refers toskeletal elements, joints, muscles, tendons, ligaments, cartilage, andskin of that subject. Particularly useful applications of the presentinvention include the prevention or treatment of pain in and aroundjoints, including shoulders, hips, knees, elbows, hands and fingers.Other particularly useful applications of the present invention includethe prevention or treatment of pain in the knee, including painresulting from osteoarthritis of the knee. Each of these may be treatedseparately, as may each of joints, muscles, tendons, ligaments,cartilage, and skin be the subject of separate treatment for pain.

As used herein, a “therapeutically effective amount” or “effectiveamount” in reference to the compounds or compositions of the instantinvention refers to an amount sufficient to induce a desired biological,pharmaceutical, or therapeutic result. That result can be alleviation ofthe signs, symptoms, or causes of a disease or disorder or condition, orany other desired alteration of a biological system. In the presentinvention, the result will involve preventing pain.

The term “topical”, as used herein, means the epicutaneous applicationof an agent to the skin.

Topical diclofenac solutions include any of the diclofenac solutionsdescribed or claimed herein (or described or claimed in U.S. Pat. Nos.4,575,515 or 4,652,557), which are useful for the transdermaladministration of diclofenac to a subject, including, for example, aformulation containing 1.5% w/w/diclofenac sodium(2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt) and45.5% w/w DMSO, and a formulation containing 1.5% w/w/diclofenac sodium(2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt),45.5% w/w DMSO ethanol, propylene glycol, glycerine, and water.

Topical diclofenac gel formulations include any one or more of thediclofenac gel formulations described or claimed herein (or described orclaimed in PCT/US2007/081674 or US Patent Application No. 20080300311),which are useful for the transdermal administration of diclofenac to asubject.

The term “transdermal”, as used herein, means the delivery of an agentinto and/or through the skin for therapy.

The terms “treating” and “treatment” mean implementation of therapy withthe intention of reducing the severity or frequency of symptoms. As usedherein, the terms “treating” and “treatment” refer to both therapeutictreatment and prophylactic or preventative measures.

A “user” means a patient, a medical care worker, or a pharmaceuticalsupplier.

Disclosed herein are methods of using topical diclofenac formulations,articles of manufacture incorporating topical diclofenac formulations,and kits. Specifically disclosed are methods of using topical diclofenacand informing users of certain preclinical and/or clinical information.

In one nonlimiting embodiment, a method is provided in which a subjectis treated for a disorder with a transdermally delivered therapeuticallyeffective amount of topical diclofenac and a user is provided with someor all of the user information described herein. In another nonlimitingembodiment, a method is provided in which a supporting body structure orthe musculoskeletal system of a subject is treated for a disorder withtopical diclofenac and a user is provided with some or all of the userinformation described herein. In another nonlimiting embodiment, thesupporting body structure is selected from joints, muscles, tendons,ligaments, cartilage and skin, and includes treatment of pain in andaround joints, including shoulders, hips, knees, elbows, hands andfingers, as well as the back, particularly the lower back. In onenonlimiting embodiment the pain is acute pain. In one nonlimitingembodiment the pain is chronic pain. In one nonlimiting embodiment thepain is treated. In another nonlimiting embodiment the pain isprevented. In one preferred nonlimiting embodiment, the pain resultsfrom osteoarthritis of the knee. Preferably, the subject is a humansubject.

In one nonlimiting embodiment, information provided to the user consistsof, consists essentially of, or comprises

-   -   1. A clinical profile for topical diclofenac including, for        example        -   a. the effects of particular QID dosing of diclofenac;        -   b. the effects of QID dosing in one or more clinical trials;        -   c. results from a 12-week, double-blind controlled trial of            topical diclofenac in a solution containing dimethyl            sulfoxide in subjects with osteoarthritis of the knee which            compared the performance of said topical diclofenac solution            against a vehicle solution containing 45.5% dimethyl            sulfoxide and a placebo solution containing 2.3% dimethyl            sulfoxide (for example, a 12-week, double-blind,            double-dummy, randomized controlled trial of topical            diclofenac in a vehicle solution containing dimethyl            sulfoxide in 775 subjects);        -   d. pharmacokinetic results from one or more studies in which            single and multiple doses of a topical diclofenac in a            vehicle solution containing dimethyl sulfoxide was applied            topically to healthy human volunteers;    -   2. An adverse event profile for a topical diclofenac, including,        for example        -   a. that concomitant use of oral NSAIDs with topical            diclofenac resulted in a higher rate of rectal hemorrhage,            and more frequent abnormal creatinine, urea and hemoglobin            (including that a combination of topical diclofenac and oral            diclofenac, compared to oral diclofenac alone, resulted in a            higher rate of rectal hemorrhage (3% vs. less than 1%), and            more frequent abnormal creatinine (12% vs. 7%), urea (20%            vs. 12%), and hemoglobin (13% vs. 9%));        -   b. that in a controlled trial, a higher rate of contact            dermatitis with vesicles was observed after treatment of 152            subjects with the combination of topical diclofenac and oral            diclofenac;        -   c. that in clinical trials; (d) the results of a clinical            study demonstrating that the addition of topical diclofenac            to oral diclofenac did not cause an elevation of liver            transaminases in osteoarthritis patients over use of oral            diclofenac alone;    -   3. A preclinical study profile for topical diclofenac,        including, for example, the results of an animal study in which        no adverse ocular effects were observed after multiple-daily        dermal application to rats for 26 weeks and minipigs for 52        weeks of DMSO at twice the concentration found in a topical        diclofenac solution (e.g., Pennsaid®);    -   4. A statement that, once dry, sunscreen, insect repellant,        lotion, moisturizer, cosmetics, and/or other topical products        can be applied to an area previously treated with a topical        diclofenac solution (e.g., Pennsaid®)        This information, which may relate, for example, to a topical        diclofenac containing 1.5% diclofenac sodium        (2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium        salt), 45.5% DMSO, ethanol, propylene glycol, glycerine, and        water, is sometimes referred to herein as the “Information.”

Other adverse event information may include that administration oftopical diclofenac does not increase the incidence of systemic adverseevents over use of oral diclofenac alone; that the addition of topicaldiclofenac to oral diclofenac does not increase the incidence ofsystemic adverse events in osteoarthritis patients; the results of aclinical study demonstrating that the addition of topical diclofenac tooral diclofenac did not increase the incidence of systemic adverseevents in osteoarthritis patients; and, the results of a clinical studyshowing that no eye lens abnormalities were observed with DMSO-vehicleor topical diclofenac solution treatment; that administration of topicaldiclofenac results in less frequent adverse events associated with theNSAID class than oral diclofenac alone; and, the results of a clinicalstudy demonstrating that the addition of topical diclofenac to oraldiclofenac did not cause an elevation of liver transaminases inosteoarthritis patients over use of oral diclofenac alone.

Other preclinical profile information may include the effect of the useof topical diclofenac on absorption of environmental toxins, including,for example, the results of a study showing that repeated application oftopical diclofenac solution did not increase systemic environmentaltoxin exposure; and the effects of use of other topical products inconjunction with topical diclofenac, including, for example, thatconcomitant use of diclofenac topical solution by repeated applicationwith other topical products, including DEET (active ingredient in insectrepellent), 2,4-D (active ingredient in commonly used pesticides) andoxybenzone (active ingredient in sunscreens) did not enhance thesystemic absorption of these products.

Other information provided to the user may include the pharmacokineticresults from one or more studies in which single and multiple doses of atopical diclofenac in a vehicle solution containing dimethyl sulfoxidewas applied topically to healthy human volunteers;

Other information provided to the user may include that the diclofenachalf life and elimination constant K_(el) for a topical diclofenacsolution comprising or consisting essentially of 1.5% diclofenac sodium,45.5% DMSO, ethanol, propylene glycol, glycerine, and water isstatistically significantly different depending on whether the solutionis applied as a single dose or as multiple doses.

In one nonlimiting embodiment, a user is provided with the Information,or with some or all of the Information, or with some or all of thetopical diclofenac clinical and preclinical information described hereinand in the Examples, for purposes of enhancing the safety profile oftopical diclofenac and/or enhancing its application to or by a subjectin need thereof.

In one nonlimiting embodiment, information provided to the usercomprises information regarding the clinical effects of dosing a topicaldiclofenac containing 1.5% diclofenac sodium (2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monosodium salt), 45.5% DMSO, ethanol,propylene glycol, glycerine, and water, including, for example, (1) theeffects of particular QID dosing of diclofenac; (2) the effects of QIDdosing in one or more clinical trials including the results from a12-week, double-blind, double-dummy, randomized controlled trial oftopical diclofenac in a vehicle solution containing dimethyl sulfoxidein 775 subjects with radiologically confirmed, symptomatic primaryosteoarthritis of the knee; (3) the effect of treating osteoarthritis ofthe knee in one or more clinical trials, including the effect oftreating one knee when both knees are affected with osteoarthritis;and/or (4) results of a human volunteer study on trans-epidermal waterloss in which no alteration in skin barrier function was observed.

In another nonlimiting embodiment, information provided comprisesinformation regarding the adverse event profile of a topical diclofenaccontaining 1.5% diclofenac sodium (2-[(2,6-dichlorophenyl) amino]benzeneacetic acid, monosodium salt), 45.5% DMSO, ethanol, propyleneglycol, glycerine, and water, including, for example (1) thatadministration of topical diclofenac does not increase the incidence ofsystemic adverse events over use of oral diclofenac alone; (2) that theaddition of topical diclofenac to oral diclofenac does not increase theincidence of systemic adverse events in osteoarthritis patients; (3) theresults of a clinical study demonstrating that the addition of topicaldiclofenac to oral diclofenac did not increase the incidence of systemicadverse events in osteoarthritis patients; and/or (4) the results of aclinical study showing that no eye lens abnormalities were observed withDMSO-vehicle or topical diclofenac solution treatment.

In yet another nonlimiting embodiment, information provided comprisesinformation regarding preclinical study results with a topicaldiclofenac containing 1.5% diclofenac sodium (2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monosodium salt), 45.5% DMSO, ethanol,propylene glycol, glycerine, and water, including, for example, (1) theeffect of the use of the topical diclofenac on absorption ofenvironmental toxins, including, for example, the results of a studyshowing that repeated application of the topical diclofenac did notincrease systemic environmental toxin exposure; and, (2) the effects ofuse of other topical products in conjunction with the topicaldiclofenac, including, for example, that concomitant use of diclofenactopical solution by repeated application with other topical products,including DEET (active ingredient in insect repellent), 2,4-D (activeingredient in commonly used pesticides) and oxybenzone (activeingredient in sunscreens) did not enhance the systemic absorption ofthese products.

In still another nonlimiting embodiment, information provided comprisesinformation regarding the clinical effects of topical diclofenac dosing,information regarding the adverse event profile of topical diclofenac,and/or information regarding preclinical study results with topicaldiclofenac, as described herein, wherein the topical diclofenac contains1.5% diclofenac sodium (2-[(2,6-dichlorophenyl) amino] benzeneaceticacid, monosodium salt), 45.5% DMSO, ethanol, propylene glycol,glycerine, and water.

In one nonlimiting embodiment, the diclofenac is in the form of atopical diclofenac solution formulation. In another nonlimitingembodiment, the diclofenac is in the form of a topical diclofenac gelformulation.

Diclofenac sodium is a benzene-acetic acid derivative that is anonsteroidal anti-inflammatory drug, designated chemically as2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt, andmay be prepared by means known in the art. See, for example, U.S. Pat.No. 4,575,515.

Following synthesis a topical diclofenac solution may be formulated bymethods known in the art as 1.5% w/w diclofenac sodium in DMSO (45.5%w/w). It is a clear, colorless to faintly pink-orange solution fortopical application. Each 1 mL of solution may contain 16.05 mg ofdiclofenac sodium. In addition, the topical diclofenac solution willpreferably contain the following inactive ingredients: propylene glycol,alcohol, glycerin and purified water.

In this disclosure, examples relating to new preclinical and clinicaldiscoveries regarding topical diclofenac are provided.

While topical non-steroidal anti-inflammatory drugs are considered safe,their long-term efficacy for osteoarthritis has been suspect. Example 1describes the results of a 12-week, double-blind, double-dummy,randomized controlled trial of a topical diclofenac solution containing1.5% diclofenac sodium (2-[(2,6-dichlorophenyl) amino] benzeneaceticacid, monosodium salt), 45.5% DMSO, ethanol, propylene glycol,glycerine, and water was conducted in 775 subjects with radiologicallyconfirmed, symptomatic primary osteoarthritis of the knee. This 5-armstudy compared the topical diclofenac solution with a placebo solution,DMSO vehicle, oral diclofenac and a combination of the topicaldiclofenac solution+oral diclofenac for relieving the signs and symptomsof knee osteoarthritis. Subjects applied study solution, 40 drops QID(four times daily), and took one study tablet daily for 12 weeks.Co-primary efficacy variables were Western Ontario McMaster UniversitiesOsteoarthritis Index (“WOMAC”) pain and physical function scores and apatient overall health assessment. Secondary variables were WOMACstiffness and patient global assessment (“PGA”) of the kneeosteoarthritis. The topical diclofenac solution was superior to placebofor pain (−6.0 vs. −4.7, P=0.015), physical function (−15.8 vs. −12.3,P=0.034), overall health (−0.95 vs. −0.37, P<0.0001), and PGA (−1.36 vs.−1.01, P=0.016), and was superior to DMSO vehicle for all efficacyvariables. The most common adverse event was dry skin (18.2%).Surprisingly, no significant difference was observed between DMSOvehicle and placebo or between the topical diclofenac solution and oraldiclofenac, yet fewer digestive system and laboratory abnormalities wereobserved with topical diclofenac than oral diclofenac. Further, additionof the topical diclofenac solution to oral diclofenac did not increasethe incidence of systemic adverse events. Additionally, administrationof topical diclofenac resulted in less frequent adverse eventsassociated with the NSAID class than oral diclofenac alone, and theaddition of topical diclofenac to oral diclofenac did not cause anelevation of liver transaminases in osteoarthritis patients over use oforal diclofenac alone. Users may be apprised of the above informationaccording to the invention. A further unexpected discovery of the study,the results for which are provided as Example 1, is that in the studythe topical diclofenac solution was applied to only one knee. Mostpatients suffer from osteoarthritis equally in both knees, yet singleknee application yielded a clinical benefit in both knees. Users orprescribers may be further apprised of this additional informationaccording to the invention.

Topical diclofenac in a DMSO vehicle is an effective treatment optionfor osteoarthritis of the knee with efficacy similar to, buttolerability better than, oral diclofenac. DMSO vehicle was no moreefficacious than placebo. According to the invention, users may beapprised of this information with regard to use of topical diclofenac,particularly with regard to the use of a topical diclofenac solutioncomprising 1.5% w/w diclofenac sodium and 45.5% w/w DMSO, which alsooptionally contains propylene glycol, alcohol, glycerin and purifiedwater as inactive ingredients.

Examples 2 and 3 describe the results of environmental toxin studies.Surprisingly in light of the efficacy of DMSO in facilitating the skinpenetration of diclofenac, these studies show that concomitant, repeateduse of a topical diclofenac solution containing 1.5% diclofenac sodium(2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt),45.5% DMSO, ethanol, propylene glycol, glycerine, and water, with othertopical products, including DEET (active ingredient in insectrepellent), 2,4-D (active ingredient in commonly used pesticides) andoxybenzone (active ingredient in sunscreens), did not enhance thesystemic absorption of these products. According to the invention, usersmay be apprised of this information with regard to use of topicaldiclofenac, particularly with regard to the use of a topical diclofenacsolution containing 1.5% diclofenac sodium (2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monosodium salt), 45.5% DMSO, ethanol,propylene glycol, glycerine, and water.

Example 4 describes the results of a transepidermal water loss (“TEWL”)study performed on human volunteers' skin. TEWL is a parameter usefulfor measuring changes to stratum corneum barrier function. Unexpectedlygiven the role of DMSO in permeabilizing the skin for diclofenac uptake,the results show no alteration in skin barrier function followingchronic use of topical diclofenac. According to the invention, users maybe apprised of this information with regard to use of topicaldiclofenac, particularly with regard to the use of a topical diclofenacsolution comprising 1.5% w/w diclofenac sodium and 45.5% w/w DMSO, whichalso optionally contains propylene glycol, alcohol, glycerin andpurified water as inactive ingredients. Users may also be informed that,before applying sunscreen, insect repellant, lotion, moisturizer,cosmetics, or other topical medication to the same skin surface, forexample, a knee, that has been treated with topical diclofenac, the usershould wait until the treated area is dry, which occurs most oftenwithin 10 minutes.

Example 5 describes the results of a study to evaluate theophthalmologic effects of topically applied DMSO in a 52-weeknon-occluded dermal toxicity study in Göttingen minipigs. It providesinformation about the ocular safety profile of dermally appliedformulations containing purified DMSO. Results showed that there was noincreased risk for development of lens opacities or changes inrefractive indices associated with DMSO. In fact no test article-relatedophthalmoscopic abnormalities were detected during the study.

Example 6 describes the results of a study to evaluate the toxicity oftest articles containing 9, 45.5, and 90% w/w DMSO after dermaladministration for 26 weeks, three times per day, and to evaluatereversibility of any observed changes following a 12-week postdoseobservation period in male and female Sprague-Dawley rats. No testarticle-related ophthalmological abnormalities were detected in anyanimal during the pretest, terminal, and recovery ophthalmoscopicexaminations.

Examples 7 and 8 describe studies to evaluate the pharmacokinetics ofdiclofenac sodium, dimethyl sulfoxide (DMSO) and dimethyl sulfone (themajor metabolite of DMSO) after a single- and multiple-dose applicationsof a topical diclofenac preparation containing 1.5% diclofenac sodium(2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt),45.5% DMSO, ethanol, propylene glycol, glycerine, and water. These dataprovide compelling evidence that the systemic exposure to diclofenaccaused by use of the topical diclofenac to treat osteoarthritis of theknee (40 drops per knee QID) is much lower than that caused by a typicaloral dose of diclofenac used in treatment of osteoarthritis (e.g., 50 mgthree times per day or “TID”). The fact that the topical diclofenac canbe shown to be comparable to oral diclofenac sodium for treatment ofosteoarthritis (see Example 1) is very surprising in view of thesefacts, especially as it is widely believed that NSAIDs, such asdiclofenac, exert their analgesic effects both locally and centrally.From the data in Example 8 it also can be computed that C_(max) oforally administered diclofenac is more than one hundred fold higher thanC_(max) for the topical diclofenac.

Example 9 describes a study to assess the drying time of a topicaldiclofenac solution containing 1.5% diclofenac sodium, 45.5% DMSO,ethanol, propylene glycol, glycerine, and water when applied topicallyto the skin surface of the knee following a single dose application,from which it can be concluded that the mean drying time for the topicaldiclofenac solution following a single dose application wasapproximately 15 minutes, with considerable variability among subjectsand dryness occurring as early as 10 minutes in most subjects. A 30minute drying time prior to the application of other topicals isconsidered safe. The results of the study further indicate that it isappropriate to instruct a user that a patient using a topical diclofenacsolution should wait at least 30 minutes after putting the topicaldiclofenac solution on the knee(s) before, for example, taking a showeror bath or otherwise wetting the knee(s).

Example 10 describes a study comparing the elimination constant aftersingle and multiple dose application of a topical solution containing1.5% diclofenac sodium and 45.5% DMSO.

Example 11 describes a multi-dose, comparative, exposure study undermaximum use conditions per labeling of both Pennsaid® Topical Solution(Diclofenac Sodium topical solution 1.5% w/w and 45.5% w/w DMSO) andSolaraze® Gel (Diclofenac Sodium 3%).

In one nonlimiting embodiment, the user is provided with information inthe form of (or substantially in the form of) the Attachment. In anothernonlimiting embodiment, the information in the Attachment is provided ina form that has been modified where appropriate to refer to the subjectproduct as a topical diclofenac gel or other formulation rather than atopical solution. In another nonlimiting embodiment, the user isprovided with information comprising or consisting essentially of in theAttachment. In another nonlimiting embodiment, the user is provided withinformation consisting essentially of the Attachment.

Many embodiments are suitable for treatment of subjects either as apreventive measure (e.g., to avoid pain) or as a therapeutic compositionto treat subjects who are suffering from acute or chronic pain. In onenonlimiting embodiment, for example, a method of treatment or preventionof pain, including pain associated with an arthritic condition, andrelated kits and articles of manufacture, comprises using a topicaldiclofenac solution or topical gel formulation described herein togetherwith some or all of the clinical and/or preclinical informationdescribed herein. Arthritic conditions include the various forms ofarthritis, including rheumatoid arthritis, osteoarthritis, andankylosing spondylitis.

Disclosed herein are topical diclofenac formulations, kits, and methodsof using topical diclofenac and topical diclofenac formulations.Specifically disclosed are methods of using topical diclofenac andinforming the user of certain information as provided herein. With theknowledge of the particular information, the administration of topicaldiclofenac to the patient can be optimized to provide safer and moreeffective use of topical diclofenac, alone or together with oraldiclofenac. As used herein, topical diclofenac formulations includetopical diclofenac solutions and topical diclofenac gel formulations,including a topical diclofenac preparation containing 1.5% diclofenacsodium (2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodiumsalt), 45.5% DMSO, ethanol, propylene glycol, glycerine, and water.

Topical diclofenac therapy can be considered optimal when combined withthe new clinical, preclinical, adverse event information provided anddescribed herein. Disclosed herein are methods of using topicaldiclofenac for transdermal administration, which may provide an increasein the safety or efficacy of topical diclofenac treatment. Extensiveresearch has been performed on administering topical diclofenac that nowreveal several developments relating to improvements in safe andeffective treatment using topical diclofenac. In certain preferredembodiments, the topical diclofenac for transdermal administration is inthe form of a solution or a gel.

In one nonlimiting embodiment, such nonlimiting information provided toa user includes the information described in Example 1, or a summarythereof.

In another nonlimiting embodiment, such nonlimiting information providedto a user includes the information described in Examples 2 and/or 3, ora summary thereof.

In another nonlimiting embodiment, such nonlimiting information providedto a user includes the information described in Example 4, or a summarythereof.

In another nonlimiting embodiment, such nonlimiting information providedto a user includes the information described in Example 5, or a summarythereof.

In another nonlimiting embodiment, such nonlimiting information providedto a user includes the information described in Example 6, or a summarythereof.

In another nonlimiting embodiment, such nonlimiting information providedto a user includes the information described in Examples 7 and/or 8, ora summary thereof.

In another nonlimiting embodiment, such nonlimiting information providedto a user includes the information described in Example 9, or a summarythereof.

In another nonlimiting embodiment, such nonlimiting information providedto a user includes the information described in Example 10, or a summarythereof.

In another nonlimiting embodiment, such nonlimiting information providedto a user includes the information described in Example 11, or a summarythereof.

In another nonlimiting embodiment, such nonlimiting information providedto a user includes the information described in two or more or all ofExamples 1-6. In another nonlimiting embodiment, such nonlimitinginformation provided to a user includes the information described in twoor more or all of Examples 1-8. In another nonlimiting embodiment, suchnonlimiting information provided to a user includes the informationdescribed in two or more or all of Examples 1-11.

In yet another nonlimiting embodiment, such nonlimiting informationprovided to a user is the information in the Attachment.

In one embodiment, such nonlimiting information provided to a user is orcomprises the information in one or more or all of Sections 6 (“AdverseReactions”), 7.8 (“Oral Nonsteroidal Anti-inflammatory Drugs”), 7.9(“Topical Treatments”), 12.3 (“Pharmacokinetics), 13.2 (“AnimalToxicology and/or Pharmacology”) and 14 (“Clinical Studies”) of theAttachment.

Topical diclofenac can be formulated for administration where theformulation generally contains DMSO and one or more pharmaceuticallyacceptable excipients. As used herein, “pharmaceutically acceptableexcipient” means any other component added to the pharmaceuticalformulation other than the diclofenac and the DMSO. Excipients may beadded to facilitate manufacture, enhance stability, control release,enhance product characteristics, enhance bioavailability, enhancepatient acceptability, etc. Pharmaceutical excipients include, forexample, carriers, fillers, binders, disintegrants, lubricants,glidants, colors, preservatives, suspending agents, dispersing agents,film formers, buffer agents, pH adjusters, preservatives etc.

In certain embodiments, the diclofenac is in the form of apharmaceutically acceptable salt or free acid. Examples ofpharmaceutically acceptable salts include metal salts, including alkalimetal, alkaline earth metal, and nitrogen-based salts, such as ammoniumsalts. Sodium, potassium, epolamine and diethylamine salts arepreferred. In one preferred embodiment the diclofenac is diclofenacmonosodium salt.

In one nonlimiting embodiment, the topical diclofenac is a solution.

In another nonlimiting embodiment, the topical diclofenac is a gel.

In one embodiment, the topical diclofenac is 1.5% w/w diclofenac sodiumin a vehicle solution containing DMSO 45.5% w/w and other excipients. Inone aspect of this embodiment, the other excipients comprise propyleneglycol, alcohol, glycerin and purified water.

In one nonlimiting embodiment, the topical diclofenac is a gelformulation according to PCT/US2007/081674 (International PublicationNo. WO 2008/049020 A2), the contents of which are incorporated herein intheir entirety by this reference. The topical diclofenac may be any ofthe gel formulations described or claimed therein. In anothernonlimiting embodiment, the topical diclofenac is a gel formulationaccording to US Patent Application No. 20080300311 (published Dec. 4,2008), the contents of which are incorporated herein in their entiretyby this reference. The topical diclofenac may be any of the gelformulations described or claimed therein.

In another nonlimiting embodiment, the topical diclofenac is a gelformulation comprising diclofenac sodium, dimethyl sulfoxide, ethanol,propylene glycol, one or more thickening agents, and water. In oneaspect of this embodiment, the topical diclofenac gel formulationfurther comprises glycerol. In another aspect, the thickening agent isselected from the group consisting of cellulose polymers, carbomerpolymers, a carbomer derivative, a cellulose derivative, polyvinylalcohol, poloxamers, polysaccharides, and mixtures thereof.

In another nonlimiting embodiment, the topical diclofenac is a gelformulation comprising or consisting essentially of 1-5% w/w diclofenacsodium; 30-60% w/w dimethyl sulfoxide; 1-50% w/w ethanol; 1-15% w/wpropylene glycol; a thickener; and water (added to make 100% w/w). In apreferred aspect of this embodiment, the gel formulation has a viscosityof 10-50,000 centipoise.

In another nonlimiting embodiment, the topical diclofenac is a gelformulation comprising or consisting essentially of about 2% w/wdiclofenac sodium; about 45.5% w/w dimethyl sulfoxide; about 23-29% w/wethanol; about 11% w/w propylene glycol; about 0-6% w/whydroxypropylcellulose (HY119); and water (added to make 100% w/w). In apreferred aspect of this embodiment, the gel formulation has a viscosityof 500-5,000 centipoise.

In another nonlimiting embodiment, the topical diclofenac is a gelformulation comprising or consisting essentially of diclofenac sodium ata concentration selected from the group consisting of 1, 1.5, 2 and 3%w/w; dimethyl sulfoxide at a concentration selected from the groupconsisting of 42, 43, 44, 45, 45.5 46, 47, 48 and 49% w/w and fractionsin between; ethanol at 23-29% w/w; propylene glycol at a concentrationselected from the group consisting of 9, 10, 11, 12, 13% w/w andfractions in between; hydroxypropylcellulose (HY119) at 0-6% w/w; andwater (included in an amount sufficient to make 100% w/w). In apreferred aspect of this embodiment, the gel formulation has a viscosityof about 500-5000 centipoise.

In certain embodiments, the above-described topical diclofenac gelformulations include 1-5% glycerol. In such embodiments, the gelformulation will have a drying rate and a transdermal flux that aregreater than a comparative liquid topical diclofenac formulation. Inother embodiments, the above-described topical diclofenac gelformulations will have a pH of about 6.0 to about 10.0.

In another nonlimiting embodiment, the topical diclofenac is a gelformulation comprising diclofenac sodium, ethanol, DMSO, propyleneglycol, hydroxypropylcellulose and water. In one aspect of thisembodiment, the hydroxypropylcellulose is substituted withalklycellulose, hydroxyalkylcellulose, carboxyalkylcellulose, or sodiumcarboxyalklycellulose, where alkyl is methyl, ethyl or propyl, or amixture thereof. In a further aspect of this embodiment, the saidalklycellulose, hydroxyalkylcellulose, carboxyalkylcellulose, or sodiumcarboxyalklycellulose is replaced in whole or in part by an acrylicpolymer (for example, Carbopol polymers, Noveon polycarbophils andPemulen polymeric emulsifiers available commercially from Noveon Inc. ofCleveland, Ohio), an acrylic polymer derivative, a cellulose polymerderivative, polyvinyl alcohol (“PVA”), polyvinylpyrrolidone (“PVP”), apoloxamer, a polysaccharide, or a mixture thereof.

In another aspect, gel formulations useful in the invention are NSAIDgel formulations, such as a topical diclofenac gel formulation, andcomponents of the formulations are as follows: The gel formulationscomprise an active agent, preferably a non-steroidal anti-inflammatorydrug or pharmaceutically acceptable salts thereof. More preferably, thenon-steroidal anti-inflammatory is diclofenac in the form of apharmaceutically acceptable salt or free acid. Examples ofpharmaceutically acceptable salts include metal salts, including alkalimetal, alkaline earth metal, and nitrogen-based salts, such as ammoniumsalts. Sodium, potassium, epolamine and diethylamine salts arepreferred. In one preferred embodiment the diclofenac is diclofenacmonosodium salt.

In a preferred embodiment, the sodium salt of diclofenac is used.Diclofenac may be present in a range of approximately 0.1% to 10%, suchas 1, 2, 3, 4, or 5% w/w. In another embodiment, the present inventionincludes a penetration enhancer. The penetration enhancer may bedimethyl sulfoxide (“DMSO”) or derivatives thereof. The DMSO may bepresent in an amount by weight of 1% to 70%, and more preferably,between 25% and 60%, such as 25, 30, 40, 45, 50, 55, or 60% w/w.Preferably, DMSO is used in the present invention at a concentration ofabout 40 to about 50% w/w, such as 41, 42, 43, 44, 45, 46, 47, 48, 49and 50% and all fractions in between such as 44, 44.5, 45, 45.5, 46,46.5%, and the like. In certain embodiments, the gel formulationincludes a lower alkanol, such as methanol, ethanol, propanol, butanolor mixtures thereof. In certain embodiments, the alkanol is present atabout 1 to about 50% w/w. Preferably, ethanol is used at about 1-50%w/w, such as 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% w/w, and allfractions in between. In certain embodiments, the gel formulationincludes a polyhydric alcohol, such as a glycol. Suitable glycolsinclude ethylene glycol, propylene glycol, butylene glycol, dipropyleneglycol, hexanetriol and a combination thereof. Preferably, propyleneglycol is used at about at 1-15% w/w, such as 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, or 15% w/w, and all fractions in between. In certainembodiments, the gel formulation includes glycerol (also referred to asglycerine) at a concentration of 0-12% w/w. Preferably, glycerol is usedat 0-4% w/w, such as 0, 1, 2, 3, or 4% w/w, and all fractions inbetween. In some embodiments, no glycerol is used in the formulation. Ina preferred embodiment, the gel formulation provides comprises adiclofenac solution and at least one thickening agent to make a gel. Theat least one thickening agent of the present invention may be an acrylicpolymer (for example, Carbopol polymers, Noveon polycarbophils andPemulen polymeric emulsifiers available commercially from Noveon Inc. ofCleveland, Ohio), an acrylic polymer derivative, a cellulose polymer, acellulose polymer derivative, polyvinyl alcohol, poloxamers,polysaccharides or mixtures thereof. Preferably the at least onethickening agent is hydroxypropylcellulose (HPC) used such that the endviscosity is between 10 and 50000 centipoise (cps). More preferably theend viscosity is between 500 and 20000 cps. The gel formulation mayoptionally include at least one antioxidant and/or one chelating agent.Preferred antioxidants may be selected from the group consisting ofbutylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyllinoleate, ascorbyl dipalmitate, ascorbyl tocopherol maleate, calciumascorbate, carotenoids, kojic acid, thioglycolic acid, tocopherol,tocopherol acetate, tocophereth-5, tocophereth-12, tocophereth-18,tocophereth-80, and mixtures thereof. Preferred chelating agents may beselected from the group consisting of ethylenediamine tetraacetic acid(EDTA), diammonium EDTA, dipotassium EDTA, calcium disodium EDTA, HEDTA,TEA-EDTA, tetrasodium EDTA, tripotassium EDTA, trisodium phosphate,diammonium citrate, galactaric acid, galacturonic acid, gluconic acid,glucuronic acid, humic acid, cyclodextrin, potassium citrate, potassiumethylenediaminetetramethylenephosphonic acid (“EDTMP”), sodium citrate,sodium EDTMP, and mixtures thereof. In addition, the topical gelformulations can also comprise a pH adjusting agent. In one particularembodiment, the pH adjusting agent is a base. Suitable pH adjustingbases include bicarbonates, carbonates, and hydroxides such as alkali oralkaline earth metal hydroxide as well as transition metal hydroxides.Alternatively, the pH adjusting agent can also be an acid, an acid salt,or mixtures thereof. Further, the pH adjusting agent can also be abuffer. Suitable buffers include citrate/citric acid buffers,acetate/acetic acid buffers, phosphate/phosphoric acid buffers,formate/formic acid buffers, propionate/propionic acid buffers,lactate/lactic acid buffers, carbonate/carbonic acid buffers,ammonium/ammonia buffers, and the like. The pH adjusting agent ispresent in an amount sufficient to adjust the pH of the composition tobetween about pH 4.0 to about 10.0, more preferably about pH 7.0 toabout 9.5. In certain embodiments, the unadjusted pH of the admixedcomponents is between 8 and 10, such as 9, without the need for theaddition of any pH adjusting agents.

The present invention includes a method for applying multiple topicalagents to a subject with pain comprising topically administering apharmaceutical composition comprising a therapeutically effective amountof a topical diclofenac in DMSO, waiting for the treated area to dry(the time of which can be dependent on individual skin characteristics,environmental conditions such as temperature and humidity, and surfacearea, often about 5-30 minutes, about 5-20 minutes, for example, andtypically about 10 minutes or less for a topical diclofenac preparation,including a topical diclofenac solution as described in the Examples),and applying another topical agents. In one nonlimiting embodiment, thesubject has osteoarthritis. In another nonlimiting embodiment, thesubject has osteoarthritis of the knee. In one embodiment, the topicalagent administered after the topical diclofenac is a sunscreen or aninsect repellant. In another nonlimiting embodiment, the inventionincludes a method of protecting a subject with osteoarthritis from UVexposure and alleviating the signs and symptoms of osteoarthritis in thesubject comprising the steps of applying a therapeutically effectiveamount of a topical diclofenac in DMSO; waiting for the treated area todry (the time of which can be dependent on individual skincharacteristics, environmental conditions such as temperature andhumidity, and surface area, often about 5-30 minutes, about 5-20minutes, for example, and typically about 10 minutes or less for atopical diclofenac preparation, including a topical diclofenac solutionas described in the Examples), applying sunscreen to the same area oftreatment.

Also included herein are pharmaceutical products (kits) useful, forexample, for the treatment or prevention of pain, including pain causedby arthritis, such as osteoarthritis, for example, which comprise one ormore containers containing a topical diclofenac formulation andinformation or published material, e.g., as product inserts or productlabels. The information can indicate quantities of the components to beadministered, guidelines for administration, safety issues, and thelike, all as disclosed and provided herein.

The kits may further comprise one or more conventional pharmaceuticalkit components, such as, for example, one or more containers to aid infacilitating compliance with a particular dosage regimen, etc. Exemplarykits can be in the form of a package. Suitable packages and packagingare known in the art or easily ascertained by one of ordinary skill inthe art.

In one nonlimiting embodiment, the topical diclofenac formulation ispackaged with information informing the user that the topical diclofenacsolution will not cause an uptake of one or more environmental toxins.In another nonlimiting embodiment, the topical diclofenac formulation ispackaged with information that includes reference to a lack ofanticipated or expected adverse events or adverse reactions in patientsfrom exposure to one or more environmental toxins following the acuteand/or chronic use of a topical diclofenac solution, for example atopical diclofenac preparation containing 1.5% diclofenac sodium(2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt),45.5% DMSO, ethanol, propylene glycol, glycerine, and water.

In one nonlimiting embodiment, a method of manufacturing a topicaldiclofenac pharmaceutical product comprises packaging a topicaldiclofenac dosage form with the Information. Additional information caninclude the information disclosed, summarized or otherwise providedherein, including the information provided in any of Examples 1-4.

In another nonlimiting embodiment, an article of manufacture comprises acontainer containing a dosage form of topical diclofenac, wherein thecontainer is associated with published material informing the user ofsome of all of the Information. Additional information can include theinformation disclosed, summarized or otherwise provided herein,including the information provided in any of Examples 1-4.

In one nonlimiting embodiment of the methods and articles of manufactureprovided herein, a topical diclofenac dosage form can comprise about 40drops per knee, QID. In one aspect of this embodiment, a diclofenac oraldosage form may also be provided or recommended or included within themethods and articles of manufacture provided herein. In anothernonlimiting embodiment of the methods and articles of manufactureprovided herein, a topical diclofenac dosage form can compriseapplication of a topical diclofenac gel formulation twice daily.

In another nonlimiting embodiment of the methods and articles ofmanufacture provided herein, a kit of information concerning a topicaldiclofenac product comprising diclofenac and dimethyl sulfoxide isprepared and/or provided, said kit comprising information about (a)clinical effects of dosing of a topical diclofenac solution comprising1.5% w/w diclofenac sodium and 45.5% w/w dimethyl sulfoxide, including(i) the effects of 40-drop QID dosing of said topical diclofenacsolution; (ii) the effects of 40-drop QID dosing of said topicaldiclofenac solution in one or more clinical trials; (iii) results from a12-week, double-blind, controlled trial of said topical diclofenacsolution in subjects with osteoarthritis of the knee which compared theperformance of said topical diclofenac solution against a vehiclesolution containing 45.5% dimethyl sulfoxide and a placebo solutioncontaining 2.3% dimethyl sulfoxide; and (iv) pharmacokinetic resultsfrom one or more studies in which single and multiple doses of a topicaldiclofenac in a solution containing dimethyl sulfoxide was appliedtopically to healthy human volunteers; (b) an adverse event profile fora topical diclofenac solution comprising 1.5% w/w diclofenac sodium and45.5% w/w dimethyl sulfoxide, including, (i) concomitant use of oralNSAIDs with topical diclofenac resulted in a higher rate of rectalhemorrhage, more frequent abnormal creatinine, urea and hemoglobin; (ii)that in a controlled trial, a higher rate of contact dermatitis withvesicles was observed after treatment of 152 subjects with thecombination of topical diclofenac and oral diclofenac; and (iii) resultsof a clinical study demonstrating that the addition of said topicaldiclofenac solution to oral diclofenac did not cause an elevation ofliver transaminases over use of oral diclofenac alone; (c) preclinicalstudy results for a topical formulation comprising dimethyl sulfoxide,including for example, the results of an animal study in which noadverse ocular effects were observed after multiple-daily dermalapplication to rats for 26 weeks and minipigs for 52 weeks of DMSO attwice the concentration found in a topical diclofenac solution (e.g.,Pennsaid®); and (d) a statement that, once dry, sunscreen, insectrepellant, lotion, moisturizer, cosmetics, and/or other topical productscan be applied to an area previously treated with a topical diclofenacsolution (e.g., Pennsaid®).

Yet another nonlimiting embodiment is a method of obtaining marketingauthorization from a regulatory authority for a topical diclofenacproduct comprising referencing the kit of information.

In another embodiment, a method for distribution of a topical diclofenacproduct is provided, comprising the steps of (a) obtaining marketingauthorization from a regulatory authority for a topical diclofenacproduct comprising referencing said kit of the invention; and providingsaid topical diclofenac product to one or more distributors.

The following examples further illustrate the invention but, of course,are not to be construed as in any way limiting its scope.

EXAMPLES Example 1 12-Week, Double-Blind, Double-Dummy, RandomizedControlled Trial of Topical Diclofenac Solution

This Example describes novel clinical information that may, for example,be provided to a user according to the present invention, comprisingsafety and efficacy results from a 12-week, double-blind, double-dummy,randomized controlled trial of a topical diclofenac preparationcontaining 1.5% diclofenac sodium (2-[(2,6-dichlorophenyl) amino]benzeneacetic acid, monosodium salt), 45.5% DMSO, ethanol, propyleneglycol, glycerine, and water (“Topical Diclofenac Solution”) in 775subjects with radiologically confirmed, symptomatic primaryosteoarthritis of the knee. The study included a placebo arm toestablish efficacy, a DMSO vehicle arm to address possible DMSOefficacy, an oral diclofenac arm for comparison with the topicaldiclofenac solution, and a combination of Topical Diclofenac Solutionplus oral diclofenac to assess combined treatment.

Study Subjects:

This randomized, double-blind, double-dummy, placebo-, vehicle- andactive-controlled study was conducted at 40 outpatient centers in Canadaand 21 centers in the United States following approval by theappropriate institutional review boards. Eligible subjects, afterwritten informed consent, included men and non-pregnant women aged 40-85with primary OA of the knee based on (i) standard radiological criteriafor OA (Altman, R D, et al., Atlas of individual radiographic featuresin osteoarthritis. Osteoarthritis Cartilage 1995; 3 (Suppl A):3-70) on aRecent (within 3 months) examination, (ii) pain, with regular use of anNSAID or other analgesic medication (at least 3 days a week for theprevious month) and (iii) a flare of pain and minimum Likert pain scoreof 8 (40 on a scale normalized to 0-100; see below, Efficacy Measures)at baseline, following washout of that medication. A flare was definedas an increase in total Likert pain score of 25% and at least 2, and ascore of at least moderate on one or more of the five items/questions ofthe WOMAC LK3.1 pain subscale (Bellamy, N, et al., Validation study ofWOMAC: a health status instrument for measuring clinically importantpatient relevant outcomes to antirheumatic drug therapy in patients withosteoarthritis of the hip or knee. J Rheumatol. 1988 December;15(12):1833-40). All knee films were reviewed by a single radiologistand each compartment was scored (none=1, mild=2, moderate=3, severe=4).Only one knee was treated; where both knees met all entry criteria, themore painful knee (or dominant knee if they scored the same) wasselected. Standard exclusion criteria were employed, as described inRoth S H, Shainhouse J Z. Efficacy and safety of a topical diclofenacsolution (Pennsaid®) in the treatment of primary osteoarthritis of theknee: a randomized, double-blind, vehicle-controlled clinical trial.Arch Intern Med. 2004; 164:2017-23.

Study Design:

Eligible subjects were stratified by the investigator at baseline intostratum 1 (no pain and normal radiological examination in the non-studyknee) or stratum 2 (pain and/or abnormal radiological examination in thenon-study knee), and then randomized into the trial by receiving thenext numbered study kit at that clinic for that stratum. Each study kitcontained topical solution and oral tablets for one of the fivetreatment regimens: (i) Topical Diclofenac Solution [Pennsaid® TopicalSolution, Nuvo Research Inc., Mississauga, Canada] plus oral placebotablets, (ii) ‘DMSO vehicle’; vehicle solution plus oral placebo tablets(vehicle solution was the complete carrier, including 45.5% DMSO andother excipients, with no diclofenac), (iii) ‘placebo’; placebo solutionplus oral placebo tablets (placebo solution was a modified vehiclesolution with only 2.3% DMSO, for blinding purposes, and no diclofenac),(iv) ‘oral diclofenac’; placebo solution plus oral diclofenac tablets(100 mg slow release), or (v) ‘topical diclofenac+oral diclofenac’;Topical Diclofenac Solution plus oral diclofenac tablets. Subjectsapplied 40 drops of solution (approximately 1.2 mL) around the entirecircumference of the study knee, without massage, 4 times daily, andtook one study tablet daily for up to 12 weeks.

Concomitant analgesic and anti-inflammatory medications, including overthe counter NSAIDs and other analgesics, were prohibited. Continuationof stable treatment with glucosamine, chondroitin, anti-depressants or aproton pump inhibitor (previous 90 days), or low-dose (≦325 mg/day)acetylsalicylic acid (previous 30 days) was permitted. Acetaminophen wasprovided, and permitted (up to four 325-mg caplets per day) exceptduring the 3 days before each efficacy assessment. Other topicalproducts on the knee, including skin emollients, were prohibited. Apatient with a gastrointestinal adverse event was allowed to start aproton pump inhibitor. Compliance with the treatment regimen wasassessed by weighing the solution bottles and counting study tablets ateach clinic visit.

All study solutions appeared as identical clear, colorless liquids. Itwas expected that some subjects applying Topical Diclofenac Solution orDMSO vehicle would report a garlic taste or odor from exhaling dimethylsulfide, a volatile DMSO metabolite; therefore, a token amount of DMSO(2.3%) was included in the placebo solution. Previous trials withtopical diclofenac confirmed the success of this blinding procedure asthe incidence of ‘taste perversion’ adverse events was no different withplacebo solution from topical diclofenac. Oral diclofenac and placebotablets appeared identical (Novopharm® Inc.). Each study kit wasassembled according to a computer-generated randomization schedulecreated by an external statistician for each stratum using a block sizeof 5. The randomization sequence was concealed from investigators,subjects and the sponsor's clinical research personnel until after datalock.

Efficacy Measures:

Each subject completed a full efficacy assessment questionnaire afterrandomization at baseline and at 4, 8 and 12 weeks, or at drop out. Theco-primary efficacy variables (Bookman A A, et al., Effect of a topicaldiclofenac solution for relieving symptoms of primary osteoarthritis ofthe knee: a randomized controlled trial. CMAJ. 2004; 171:333-8) weredefined a priori as WOMAC pain and physical function, measured by the5-point Likert scale (Biswal S, et al., Longterm efficacy of topicalnonsteroidal anti-inflammatory drugs in knee osteoarthritis:metaanalysis of randomized placebo controlled clinical trials. JRheumatol. 2006; 33:1841-4), and patient overall health assessment(“POHA”). The POHA asked the question, “Considering all the ways yourosteoarthritic (study) knee and its treatment affect you, including bothpositive and negative effects, how would you rate your overall state ofhealth in the past 48 hours?” Secondary efficacy variables were WOMACstiffness and patient global assessment (“PGA”) of knee osteoarthritis.The PGA asked the question, “How has the osteoarthritis in your studyjoint been over the last 48 hours?” The POHA and PGA were scored on a5-point Likert scale. There was no assessment of the non-treated knee.Safety Measures: At all visits, vital signs were measured,dermatological evaluation of the study knee was done according to astandard numerical (0-4) scale (Shirley H H, et al. Efficacy and safetyof a tropical diclofenac solution (Pennsaid®) in the treatment ofprimary osteoarthritis of the knee: a randomized, double-blind,vehicle-controlled clinical trial. Arch. Intern. Med. 2004; 164:2017-23)and adverse events were solicited using open-ended questions. Adverseevents were categorized according to Coding Symbols for Thesaurus ofAdverse Reaction Terms (“COSTART”). Blood and urine samples wereobtained for routine laboratory analysis at baseline, 4 and 12 weeks.Ocular examination (visual acuity test, slit lamp examination and lensassessment) was conducted at the baseline and final visit.

Statistical Analysis Plan:

All planned analyses were specified a priori. Analysis of the Likertefficacy data was by modified intent to treat (“mITT”), excluding onlythose subjects who had no baseline data or did not administer at leastone dose of both study solution and tablets. Statistical tests weretwo-sided at the 5% level of significance. All efficacy analyses were byanalysis of covariance of the change in score from baseline to landmarkfinal assessment, with baseline score as the covariate. Subjects in bothrandomization strata were combined for all analyses.

The primary efficacy comparison was topical diclofenac vs. placebo forthe primary efficacy variables, with no correction for analysis ofmultiple primary variables (regulatory design required superiority foreach primary variable). The sample size required to show the superiorityof topical diclofenac over placebo was 142 subjects per arm, based on anestimate from previous trials of the difference (standard deviation)between groups for the change in score of 1.5 (4.5) for pain, 5.0 (15)for physical function and 0.4 (1.2) for PGA, power of 80% and Type Ierror rate of α=0.05_(2-tailed) (Baer P A, et al., Treatment ofosteoarthritis of the knee with a topical diclofenac solution: arandomised controlled, 6-week trial [ISRCTN53366886]. BMC MusculoskeletDisord. 2005; 6:44; Bookman A A, et al., Effect of a topical diclofenacsolution for relieving symptoms of primary osteoarthritis of the knee: arandomized controlled trial. CMAJ. 2004; 171:333-8; Roth S H, ShainhouseJ Z. Efficacy and safety of a Topical Diclofenac Solution (Pennsaid®) inthe treatment of primary osteoarthritis of the knee: a randomized,double-blind, vehicle-controlled clinical trial. Arch Intern Med. 2004;164:2017-23).

A post hoc sensitivity analysis of the primary efficacy data wasperformed by imputing no improvement (i.e., baseline score carriedforward and imputed as final score (“BOCF”) to non-completers by reasonof an adverse event or lack of effect and for subjects excluded frommITT.

Secondary comparisons included topical diclofenac vs. placebo for thesecondary variables, and topical diclofenac vs. DMSO vehicle and DMSOvehicle vs. placebo for all variables. A post hoc efficacy analysiscompared topical diclofenac vs. oral diclofenac and topicaldiclofenac+oral diclofenac vs. oral diclofenac. For a missing finalscore, last observation was carried forward (“LOCF”). Safety analyseswere performed on all subjects who received even one dose of eitherstudy medication. There was no imputation of missing safety data.Results were as follows.

Study Subjects:

Of 1396 subjects screened, 775 were randomized to one of the 5 treatmentarms and 527 subjects completed treatment. Over 95% of patients hadbilateral disease (pain or abnormal radiological examination also innon-study knee) with pain in the contralateral knee in 90%. A total of88% of subjects met the modified (Hochberg M C, et al., Guidelines forthe Medical Management of Osteoarthritis Part II. Osteoarthritis of theKnee. Arthritis & Rheumatism 1995; 38(1):1541-1546) American College ofRheumatology (ACR) criteria (Altman R, et al., Development of criteriafor the classification and reporting of osteoarthritis: classificationof osteoarthritis of the knee. Arthritis Rheum. 1986; 29:1039-1049) forosteoarthritis, pain and osteophytes, and the remaining had pain witheither joint space narrowing or subchondral sclerosis. Subjects in eachtreatment arm had similar demographic and baseline characteristics,duration of exposure and compliance (>89% of expected use for topicalsolution and oral tablets). Withdrawals for an adverse event weresimilar among treatment groups. Withdrawals for lack of effect weresimilar among topical diclofenac, placebo and DMSO vehicle arms, butfewer with the oral diclofenac arms.

There were 772 subjects included in the mITT group. Excluded were 3subjects who did not take at least one dose of both topical and oralmedication, or had no data. Individual subjects who omitted baselineassessment for a specific efficacy variable were excluded from thatanalysis.

Efficacy: The primary efficacy analyses, as shown in the below Table 2(“Efficacy Variable Scores”), show the superiority of topical diclofenacover placebo for the three co-primary variables—pain (P=0.015), physicalfunction (P=0.034), and POHA (P<0.0001). Superiority was observed alsofor the secondary variable PGA (P=0.016), but not for stiffness. Therewas greater improvement with topical diclofenac (P<0.05) compared toDMSO vehicle for all five variables (Table 2). A post-hoc BOCFsensitivity analysis of the primary efficacy data of all 775 patientsdid not change any of the conclusions of superiority of topicaldiclofenac compared with placebo (pain, P=0.031; physical function,P=0.041; POHA, P=0.0001).

TABLE 2 Efficacy variable scores^(a) P value TDiclo TDiclo TDicloTDiclo + vs. vs. vs. TDiclo^(b) placebo^(b) DMSO^(b) ODiclo^(b)ODiclo^(b) placebo DMSO ODiclo WOMAC Pain (n = 154) (n = 155) (n = 161)(n = 151) (n = 151) Baseline score 13.2 (3.4) 12.9 (3.3) 13.0 (3.2) 13.2(3.0) 13.2 (3.4) Change in score^(c) −6.0 (4.5) −4.7 (4.4) −4.7 (4.3)−6.4 (4.1) −7.0 (4.8) 0.015 0.009 0.429 WOMAC (n = 154) (n = 153) (n =161) (n = 151) (n = 150) Physical Function Baseline score 41.7 (12.8)41.6 (11.7) 41.4 (11.4) 42.1 (12.0) 41.0 (11.2) Change in score^(c)−15.8 (15.1) −12.3 (14.7) −12.1 (14.6) −17.5 (14.3) −18.7 (14.0) 0.0340.026 0.319 POHA (n = 154) (n = 152) (n = 160) (n = 150) (n = 148)Baseline 2.34 (1.02) 2.22 (1.03) 2.30 (1.14) 2.23 (1.12) 2.19 (1.04)Change in score^(c) −0.95 (1.30) −0.37 (1.04) −0.65 (1.12) −0.88 (1.31)−0.95 (1.21) <0.0001 0.016 0.956 PGA (n = 154) (n = 153) (n = 161) (n =151) (n = 150) Baseline 3.12 (0.78) 3.04 (0.82) 3.13 (0.74) 3.04 (0.87)3.08 (0.81) Change in score^(c) −1.36 (1.19) −1.01 (1.18) −1.07 (1.10)−1.42 (1.29) −1.53 (1.27) 0.016 0.018 0.439 WOMAC (n = 154) (n = 153) (n= 161) (n = 151) (n = 150) Stiffness Baseline 5.14 (1.63) 5.01 (1.70)5.12 (1.61) 5.21 (1.72) 5.07 (1.53) Change in score^(c) −1.93 (2.01)−1.52 (2.05) −1.48 (2.07) −2.07 (2.02) −2.30 (2.00) 0.112 0.035 0.596Abbreviations: TDiclo, Topical Diclofenac Solution plus oral placebo;placebo, topical placebo plus oral placebo; DMSO, topical dimethylsulfoxide-containing vehicle plus oral placebo; ODiclo, oral diclofenacplus topical placebo; TDiclo + ODiclo, Topical Diclofenac Solution plusoral diclofenac; WOMAC, Western Ontario McMaster Universities LK3.1Osteoarthritis Index; POHA, patient overall health assessment; PGA,patient global assessment of the study knee ^(a)Data are presented asmean (SD). Maximum score for pain, 20; physical function, 68; POHA andPGA, 4; stiffness, 8. ^(b)The number of subjects (n) varied by efficacyparameter because individual subjects did not submit a full baselineassessment. ^(c)Final score minus baseline scoreAdditionally, the Efficacy Variable Score shows that no significantefficacy advantage of the DMSO vehicle over placebo was observed for theprimary or secondary variables, except for the POHA. Furthermore, acomparison of oral diclofenac vs. topical diclofenac found nostatistical difference for any of the 5 efficacy variables. Thecombination of topical diclofenac+oral diclofenac was no better thanoral diclofenac alone for all variables (pain, P=0.30; physicalfunction, P=0.33; POHA, P=0.43; stiffness, P=0.16; PGA, P=0.50).

Mean [SD] acetaminophen use with topical diclofenac (0.64 [0.83] capletsper day) was lower than with placebo (0.95 [1.14], P=0.005) and DMSOvehicle (0.99 [1.11], P=0.002), and was not different than that for oraldiclofenac (0.55 [0.82], P=0.41) or topical diclofenac+oral diclofenac(0.46 [0.70]; P=0.10).

Safety:

Skin adverse events predominated with topical diclofenac, most being dryskin. The overall incidence of skin adverse events was similar intopical diclofenac+oral diclofenac, and lower in placebo, and oraldiclofenac arms. The rate with DMSO vehicle was intermediate betweentopical diclofenac and placebo. Only 5 (3.2%) subjects in topicaldiclofenac withdrew due to an application site reaction. Importantly, asshown in the below Table 3 (“Incidence of Adverse Events”) the incidenceof adverse events of the digestive system with topical diclofenac was nogreater than placebo and much lower than oral diclofenac and topicaldiclofenac+oral diclofenac. Withdrawal due to a digestive system adverseevent was higher in oral diclofenac (11 [7.3%]) vs. topical diclofenac(4 [2.6%]) and placebo (3 [1.9%]). Additionally, as shown in the belowTable 3, the combination topical diclofenac+oral diclofenac did notincrease the incidence of digestive system events over oral diclofenacalone.

TABLE 3 Incidence of adverse events^(a) TDiclo + TDiclo placebo DMSOODiclo ODiclo (n = 154) (n = 157) (n = 161) (n = 151) (n = 152) AdverseEvent Any adverse event 96 (62.3) 90 (57.3) 97 (60.2) 94 (62.3) 98(64.5) Abnormal taste sensation or odor 0 (0.0) 1 (0.6) 1 (0.6) 0 (0.0)1 (0.7) Any digestive system event 10 (6.5) 15 (9.6) 18 (11.2) 36 (23.8)39 (25.7) Abdominal pain 5 (3.2) 1 (0.6) 5 (3.1) 11 (7.3) 3 (2.0)Dyspepsia 4 (2.6) 6 (3.8) 6 (3.7) 6 (4.0) 5 (3.3) Diarrhea 2 (1.3) 3(1.9) 2 (1.2) 7 (4.6) 12 (7.9) Liver function tests abnormal 3 (1.9) 1(0.6) 6 (3.7) 12 (7.9) 11 (7.2) Rectal hemorrhage 1 (0.6) 0 (0.0) 0(0.0) 0 (0.0) 5 (3.3) Nausea 0 (0.0) 0 (0.0) 1 (0.6) 3 (2.0) 5 (3.3) Anyskin/appendages event 41 (26.6) 12 (7.6) 27 (16.8) 11 (7.3) 47 (30.9)Dry skin (application site) 28 (18.2) 5 (3.2) 18 (11.2) 4 (2.6) 30(19.7) Contact dermatitis (application site) 4 (2.6) 1 (0.6) 5 (3.1) 1(0.7) 12 (7.9) Rash 4 (2.6) 0 (0.0) 2 (1.2) 0 (0.0) 0 (0.0) Contactdermatitis with vesicles 3 (1.9) 0 (0.0) 0 (0.0) 1 (0.7) 6 (3.9)(application site) Pruritis (application site) 2 (1.3) 0 (0.0) 0 (0.0) 0(0.0) 1 (0.7) Other system event^(b) Headache 27 (17.5) 18 (11.5) 21(13.0) 26 (17.2) 21 (13.8) Back pain 15 (9.7) 10 (6.4) 15 (9.3) 11 (7.3)4 (2.6) Arthralgia 14 (9.1) 15 (9.6) 25 (15.5) 12 (7.9) 7 (4.6) Pain 7(4.5) 5 (3.2) 11 (6.8) 8 (5.3) 1 (0.7) Respiratory disorder 5 (3.2) 6(3.8) 4 (2.5) 8 (5.3) 7 (4.6) Accidental injury 4 (2.6) 6 (3.8) 7 (4.3)4 (2.6) 6 (3.9) Abnormal vision 4 (2.6) 5 (3.2) 4 (2.5) 4 (2.6) 1 (0.7)Conjunctivitis 4 (2.6) 1 (0.6) 0 (0.0) 3 (2.0) 0 (0.0) Abbreviations:TDiclo, Topical Diclofenac Solution plus oral placebo; placebo, topicalplacebo plus oral placebo; DMSO, topical dimethyl sulfoxide-containingvehicle plus oral placebo; ODiclo, oral diclofenac plus topical placebo;TDiclo + ODiclo, Topical Diclofenac Solution plus oral diclofenac^(a)Data are presented as number (%) of subjects. ^(b)Other adverseevents with incidence ≧2% in the TDiclo groupNo difference between treatment groups was observed for cardiovascularevents, which were <2% in each treatment group. The incidence ofhypertension was similar for all groups (1.3% for Topical DiclofenacSolution, oral diclofenac and Topical Diclofenac Solution+oraldiclofenac; 1.2% for DMSO vehicle; 0.6% for placebo). There was nodifference among the groups in reports of an abnormal taste sensation orodor, confirming the success of the blinding procedure for DMSO.

There was no serious adverse event in the Topical Diclofenac Solutionarm, 4 in placebo (1 anemia, 1 cerebrovascular accident, 1 fracturedhip, 1 dislocated prosthetic hip), 1 in DMSO vehicle (acute enteritis),1 in oral diclofenac (post-polypectomy lower gastrointestinal bleed, 8days after withdrawal of study medication) and 3 in topicaldiclofenac+oral diclofenac (1 leg cellulitis, 1 unstable angina, 1transient ischemic attack).

Changes in key NSAID-related laboratory parameters are shown in thebelow Table 4 (“Analysis of Change in Laboratory Parameters”).

TABLE 4 Analysis of change^(a) in laboratory parameters TDiclo + TDicloplacebo DMSO ODiclo ODiclo (n = 145) (n = 142) (n = 150) (n = 138) (n =141) AST Mean change, U/L −0.9 (10.3) −0.6 (5.2) 0.2 (8.5) 2.5 (10.9)4.1 (29.6) Normal to abnormal^(b), 10 (6.9) 5 (3.5) 8 (5.3) 27 (19.6) 20(14.2) N (%) ALT Mean change, U/L −1.0 (11.7) −0.3 (9.9) −0.6 (9.8) 7.2(25.3) 8.2 (68.9) Normal to abnormal, 6 (4.1) 4 (2.8) 2 (1.3) 26 (18.8)24 (17.0) N (%) Hemoglobin Mean change, g/L −1.7 (6.2) −0.8 (6.2) −0.4(6.5) −3.8 (7.1) −4.8 (6.8) Normal to abnormal, 3 (2.1) 7 (4.9) 5 (3.3)8 (5.8) 18 (12.6) N (%) Creatinine Mean change, μmol/L −0.4 (10.5) 0.8(9.0) 0.3 (10.3) 3.1 (11.0) 4.4 (11.2) Normal to abnormal, 4 (2.8) 8(5.6) 6 (4.0) 10 (7.2) 15 (10.6) N (%) Creatinine Clearance^(c) Meanchange, mL/min 0.4 (10.3) −0.5 (8.6) −0.5 (8.3) −2.4 (8.7) −3.3 (9.7)Normal to abnormal, 11 (7.6) 8 (5.7) 9 (6.0) 10 (7.2) 16 (11.4) N (%)Abbreviations: TDiclo, Topical Diclofenac Solution plus oral placebo;placebo, topical placebo plus oral placebo; DMSO, topical dimethylsulfoxide-containing vehicle plus oral placebo; ODiclo, oral diclofenacplus topical placebo; TDiclo + ODiclo, Topical Diclofenac Solution plusoral diclofenac; ALT, alanine aminotransferase; AST, aspartateaminotransferase. ^(a)Mean (SD) unless otherwise indicated. Onlysubjects with both a baseline and final lab value for the parameter areshown. ^(b)Change from normal at baseline to above upper limit of normalfor AST, ALT, creatinine, or below lower limit of normal for hemoglobin,creatinine clearance. ^(c)Calculated as per Cockcroft D W and Gault M W,Prediction of creatinine clearance from serum creatinine, Nephron 1976;16: 31-41.Overall, the mean change in the laboratory value and the number ofsubjects developing an abnormality showed no difference between topicaldiclofenac and placebo or DMSO vehicle, but a greater mean change andhigher incidence of abnormality occurred with the oral diclofenac arms.With oral diclofenac compared with topical diclofenac, there was agreater mean change in hemoglobin, alanine aminotransferase,gamma-glutamyl transpeptidase, creatinine and creatinine clearance, anda greater number of subjects developing an abnormality for theseparameters. With respect to the transaminases ALT (alanineaminotransferase) and AST (aspartate aminotransferase), there was nostatistically significant change in mean values between the oraldiclofenac and oral plus topical diclofenac treatment arms. Developmentof abnormal laboratory parameters was generally below clinicallyrelevant levels. No subject developed a clinically significant change inhemoglobin or creatinine. An increase in any liver enzyme to three timesthe upper limit of normal occurred in 1 subject with placebo, 1 withDMSO vehicle, 2 with oral diclofenac and 3 with topical diclofenac+oraldiclofenac, but none with topical diclofenac.

Ocular examination at baseline and final revealed no change in visualacuity (data not shown) and no difference in the development of lensabnormality (cataract) with placebo (4 [2.6%] subjects) vs. topicaldiclofenac (2 [1.3%]) or DMSO vehicle (6 [3.8%]).

Conclusions:

The results of this clinical study clearly show the effectiveness ofTopical Diclofenac Solution applied topically to treat the symptoms ofosteoarthritis of the knee.

Topical Diclofenac Solution was superior to both topical comparatorgroups (placebo and DMSO vehicle) for all 3 primary efficacy variables,pain, function and patient overall health. Efficacy was confirmed by aconservative BOCF sensitivity analysis.

The WOMAC physical function questionnaire asks patients to scorephysical function in areas such as difficulty descending stairs,difficulty ascending stairs, difficulty rising from sitting, difficultystanding and difficulty walking on a flat surface. The superiority oftopical diclofenac solution over placebo was surprising given that (i)the physical functions measured in the WOMAC physical functionquestionnaire are generally accomplished with the use of both knees,(ii) only one knee was treated in the study, (iii) 95% of patients haddisease in both knees (with pain in the contralateral knee occuring in90% of the study population) and (iv) the blood levels of diclofenacproduced by the topical diclofenac solution when treating one knee arefar below the levels achieved by oral administration of the drug andregarded as necessary to achieve a systemic effect (see Examples 7 and 8below). Remarkably, there was no statistical difference between topicaldiclofenac solution treatment of one knee and oral diclofenac (whichwould provide treatment for both knees) for the physical functionefficacy variable.

This study followed a typical 12-week oral NSAID trial design, namely,primary osteoarthritis of the knee with pain and abnormal radiologicalfindings. Although most subjects had bilateral osteoarthritis, only onepainful knee was treated with topical solution. Inasmuch as outcomemeasures of physical function and overall patient health assessment arelikely to be negatively influenced by symptoms in the non-treated knee,this trial design biased against Topical Diclofenac Solution. In anyoral NSAID trial, and in this study's oral diclofenac arms, subjectsautomatically treat both knees, avoiding these factors. The inclusion oforal therapy for all groups added a second placebo effect to the topicalcomparator arms, imposing a yet higher burden to prove efficacy ofTopical Diclofenac Solution over placebo. Despite these elements intrial design the efficacy of Topical Diclofenac Solution was robustlyestablished.

The response of patients in the oral diclofenac group in this study(40-48% improvement in variable score) was the same as seen in otheroral NSAID trials (Bellamy N, Buchanan W W et al., A multicenter studyof tenoxicam and diclofenac in patients with osteoarthritis of the knee.J Rheum. 1993; 20:999-1004; Yocum D, et al., Safety and efficacy ofmeloxicam in the treatment of osteoarthritis. Arch Int Med. 2000;160:2947-54), providing a powerful external audit on the validity of thetrial design and conduct, and further confirmation of the sustainedefficacy of Topical Diclofenac Solution. Topical Diclofenac Solution wasfound to be as effective as oral diclofenac at relieving the symptoms ofknee osteoarthritis with less NSAID-related systemic toxicity than oraldiclofenac. These observations support the safety and efficacy resultsof a previous equivalence study of Topical Diclofenac Solution vs. oraldiclofenac.

Claims of therapeutic efficacy for DMSO itself in osteoarthritis werediscounted in an earlier, 4-week trial with topical diclofenac (BookmanA A, et al., Effect of a topical diclofenac solution for relievingsymptoms of primary osteoarthritis of the knee: a randomized controlledtrial. CMAJ. 2004; 171:333-8) and are further disproven by this 12-weekstudy.

There was no apparent difference between Topical Diclofenac Solution andplacebo in NSAID-associated gastrointestinal adverse events (theincidence was actually lower with Topical Diclofenac Solution). In thisstudy, no eye lens abnormalities were observed with DMSO-vehicle orTopical Diclofenac Solution treatment. The combination TopicalDiclofenac Solution+oral diclofenac showed no increase in adverse eventsrelative to Topical Diclofenac Solution or oral diclofenac alone. Theblood level of diclofenac following topical application as TopicalDiclofenac Solution is only about 12 ng/mL and the incremental increasewith the combination would be negligible compared with the predictedlevel of 1500 ng/mL that is reported with oral diclofenac. Althoughcombined treatment with Topical Diclofenac Solution+oral diclofenac didnot provide a statistical advantage over oral diclofenac alone, thisregimen could be a reasonable treatment paradigm in an individual withpersistent or breakthrough knee pain despite using an oral NSAID.

In conclusion, this Example shows that Topical Diclofenac Solutionprovides durable improvement in the symptoms of osteoarthritis of theknee, and that relief is not contributed by the DMSO-carrier. Efficacyof Topical Diclofenac Solution was comparable to that achieved with oraldiclofenac. For the patient initiating pharmacological therapy forrelief of symptoms associated with osteoarthritis of the knee based oncurrent treatment guidelines, Topical Diclofenac Solution is a viable,evidence-based treatment option.

Example 2 Influence of a Topical Diclofenac Solution on PercutaneousAbsorption of Three Different Environmental Toxins after RepeatedEpicutaneous Administration to Minipigs

This Example describes novel preclinical information that may, forexample, be provided to a user according to the present invention, whichrelates to the influence of a topical diclofenac solution containing1.5% diclofenac sodium (2-[(2,6-dichlorophenyl) amino] benzeneaceticacid, monosodium salt), 45.5% DMSO, ethanol, propylene glycol,glycerine, and water (“Topical Diclofenac Solution”) on the percutaneousabsorption of three different environmental toxins, as evaluated in astudy involving repeated epicutaneous administration to minipigs.

The Test Item was Topical Diclofenac Solution [Pennsaid® TopicalSolution, Nuvo Research Inc., Mississauga, Canada]. The environmentaltoxins selected for use in the study were oxybenzone (in the form ofEqualine SPF 23 faces sunscreen; active compound 6% oxybenzone), DEET,i.e., N,N-diethyl-m-toluamide (in the form of Deep woods OFF!® pumpspray; active compound 25% N,N-diethyl-m-toluamide), and 2,4-D, i.e.,2,4-D, dimethylamine salt (in the form of Spectracide Weed Stop 2× ForLawns Concentrate; active compound 7.57% 2,4-D, dimethylamine salt). Thecontrol items used in the study were Retin-A 0.1% (tretinoin) cream,Men's Rogaine® Extra Strength Topical Solution (minoxidil 5% w/v), bothof which are approved and marketed in the United States. Both controlproducts have skin permeation enhancing capabilities and were selectedfor comparison to the Topical Diclofenac Solution in the enhancement ofenvironmental toxins. Retin-A (tretinoin) stimulates mitotic activityand increased turnover of follicular epithelial cells, resulting indisruption of the skin barrier function with consequent enhancement oftransepidermal water loss. Compromising skin barrier function can causeenhancement in permeation of molecules through the skin. The skinpermeation enhancement of Rogaine is associated with its high content ofpropylene glycol (50%), a known skin permeation enhancer.

Methods:

In this study, performed according to Good Laboratory Practices (“GLP”),18 female Göttingen Minipigs, a commonly used non-rodent species forpharmacokinetic studies, were selected for entry into the study based onthe results of a satisfactory preliminary health screening. There weresix treatment groups with 3 female animals per group. Animals wereallocated employing a pseudo-random body weight stratification procedurethat yielded groups with approximately equal mean body weight.

The Test Item and the controls were supplied ready-to-use. Toxin No. 1(sunscreen) was applied undiluted. Toxins Nos. 2 (DEET) and 3 (2,4-D)were diluted in ethanol and water, respectively, before use on test day1 according to the below dilution scheme. The same toxin administrationsolutions were used on test day 1, 21, 28 and 35. Between theadministrations, the solutions were stored at +2° C. to +4° C.

Preparation of the Toxin Administration Dose

Targeted Volume of Strength of exposure of diluted toxin active cmpdactive cmpd Dilution to be applied Toxin Active in the toxin to 150 cm²of the to 150 cm² No. compound (w/v) [μg] toxin [mL] 1 oxybenzone   6%300000 1 5 2 DEET  25% 6723 40 1.08 3 2,4-D 7.57% 13.35 5000 0.88

Toxin was applied by epicutaneous administration via syringe onto theback region. There was a single administration on test day 1 (beforeadministration of the Test Item or the Controls) and singleadministration on days 21, 28 and 35 (after administration of the TestItem or the Controls). The administration area was 150 cm²/animal. Theadministration site was situated on the animal's back between the foreand the hind extremities. The surface area of the application site wasselected to provide a high toxin exposure that would ensure measurablesystemic levels of the toxins.

Prior to the start of the study, the administration sites were clearedof bristles, if present. The remaining hairs were clipped. The toxin wasspread onto the administration area using a syringe. The administrationarea was not covered with any dressing. Following administration theanimals were restrained for at least 1 hour (until the toxin hadcompletely dried) in slings which allowed free movement of the head butprevented a complete body turn in order to prevent access by the animalsto the toxins.

The six treatment groups were assigned to receive toxins, Test Items andControls as set forth in the following table.

Group Toxin No. (Name) Test Item/Control 1 1 (oxybenzone) TopicalDiclofenac Solution (Test Item) 2 2 (DEET) Topical Diclofenac Solution(Test Item) 3 3 (2,4-D) Topical Diclofenac Solution (Test Item) 4 1(oxybenzone) Retin-A (Control no. 1) 5 2 (DEET) Rogaine ® (Control no.2) 6 3 (2,4-D) Rogaine ® (Control no. 2)

On test day 21, Topical Diclofenac Solution (Test Item) or RogaineTopical Solution (Control No. 2), respectively, was applied 30 minutesbefore toxin administration based on a pre-specified schedule. Noadministration of Retin-A (Control No. 1) was scheduled for test day 21.On test day 21 the toxin administration was carried out after the TestItem/Control administration according to the following schedule: Groups1, 2 and 3: 30 minutes after Test Item/Control administration; Group 4:after an overnight break; Groups 5 and 6: 30 minutes after TestItem/Control administration.

In sum, Test Item/Control application was as follows: Topical DiclofenacSolution (Test Item), 0.22 mL/administration site four times daily fromtest days 6 to 20 (7:30, 12:30, 17:30, 22:30) and one single dose on day21 (7:30); Retin-A 0.1% cream (Control No. 1), 112.5 mg/administrationsite once daily from test days 6 to 20 (22:30); Rogaine ES (Control No.2), 0.8 mL/administration site twice daily from test days 6 to 20 (7:30,17:30) and one single dose on day 21 (7:30). The administration site ofthe Test Item or Controls was exactly the same as for the toxins, i.e.150 cm² on the animal's back between the fore and hind extremities, asnoted above. Toxin dose levels were selected based upon available humanenvironmental and occupational exposure data. Dose levels for the TestItem or Controls were based on the recommended doses of the products inhumans.

The Test Item or Control was spread onto the administration area using asyringe. The administration area was not covered with any dressing.Following administration the animals were restrained for at least 1 hour(until the test item and controls had completely dried) in slings whichallowed free movement of the head but prevented a complete body turn inorder to prevent access by the animals to the Test Item or Controls.

Any contact of the test areas with water was avoided throughout thewhole experiment.

Observations:

Observations related to individual animals made throughout the studyincluded clinical signs, body weight and food/water consumption.

For evaluation of local tolerance, skin reactions were examined oncedaily throughout the study, prior to each administration (end of therespective exposure period), if applicable. Reactions, namely, erythema,eschar and oedema formation were scored based on Draize J H, Appraisalof the Safety of Chemicals in Food, Drugs and Cosmetics, Association ofFood and Drug Officials of the United States, Austin, Tex., 1959. Anyother lesions were also recorded, if any occurred.

Blood sampling for pharmacokinetics was undertaken for each animal atpredetermined sampling times and processed for at least 2 mL Li-Heparinplasma/sample, which were split into two aliquots of 1 mL each.

The area under the concentration-time curve (“AUC”) from time zero to 48h, AUC_(0-48h), for each toxin was calculated for each minipig aftereach toxin administration on test days 1, 21, 28 and 35 using a lineartrapezoid method. Descriptive statistics (arithmetic mean, standarddeviation) of non-transformed AUC_(0-48h) and natural log-transformedAUC_(0-48h) were calculated for each treatment group for theadministration days on test days 1, 21, 28 and 35. Log-transformedAUC_(0-48h) were compared using the repeated measurements employing ageneralized linear model of variance using treatment group andadministration day as covariates. The achievement of steady state ofdiclofenac was assessed by using repeated measurements employinganalysis of variance (“ANOVA”) with log-transformed troughconcentrations on test days 19, 20 and 21. All statistical analyses weretwo-sided and in all analyses the Type I (alpha) error was fixed at the5% level.

Results:

With regard to clinical signs, no signs of local intolerance reactionswere observed in any of the minipigs after repeated epicutaneousadministration of 0.22 mL Topical Diclefenac Solution/animal (approx.3.5 mg diclofenac sodium/animal) and any of the Toxin Nos. 1, 2 or 3.Additionally, no signs of local intolerance reactions were observed inany of the minipigs after repeated epicutaneous administration of eitherControl No. 1 or Control No. 2.

Additionally, no signs of systemic intolerance reactions were observedin any of the minipigs after repeated epicutaneous administration of0.22 mL Topical Diclofenac Solution/animal (approx. 3.5 mg diclofenacsodium/animal) and any of the three toxins. No signs of systemicintolerance reactions were observed in any of the minipigs afterrepeated epicutaneous administration of either 112.5 mg Retin-A 0.1%(tretinoin) cream/animal (control no. 1) or 0.8 mL Men's Rogaine® ExtraStrength Topical Solution/animal (control no. 2) and any of the threetoxins.

The body weight was in the normal range throughout the course of thestudy in all animals after repeated epicutaneous administration of 0.22mL Topical Diclofenac Solution/animal (approx. 3.5 mg diclofenacsodium/animal) or the two controls and any of the three toxins.

No influence on the food consumption was noted for any of the animalsafter repeated epicutaneous administration of 0.22 mL Topical DiclofenacSolution/animal (approx. 3.5 mg diclofenac sodium/animal) or the twocontrols and any of the three toxins.

The visual appraisal of the drinking water consumption did not revealany Test Item-related influence.

Pharmacokinetic data results indicated that systemic diclofenac steadystate was reached by day 19.

Due to limitation in the sensitivity of the analytical methods employedin the study, no DEET (Toxin no. 2) or 2,4-D (Toxin no. 3) could bequantified in plasma for any of the animals treated with the TopicalDiclofenac Solution or the Rogaine so no firm conclusions could be drawnfrom the study concerning the enhancement of systemic absorption ofthese toxins. A subsequent study (described in Example 3 below) usinghigher concentrations of DEET and 2,4-D was therefore conducted.

In contrast, the exposure to oxybenzone could be well quantified on allapplication days. The courses of the plasma concentrations of oxybenzonewere summarized non-compartmentally by means of C_(max) (maximumobserved plasma concentration), tmax (time of C_(max) after applicationof the toxin), and the AUC₀₋₄₈ (the trapezoidal area under the timecourse of the plasma concentrations up to 48 hours after application).

Based on the ANOVA of the log-transformed AUC₀₋₄₈, the area exposure tooxybenzone for the animals treated with Topical Diclofenac Solution wasstatistically significantly lower (p≦0.05) on days 21, 28 and 35compared with the animals treated with the control (Retin-A), whereasthere was no statistically significant difference between the treatmentsgroups on day 1 (before the start of the treatments with the test andcontrol items). No statistically significant differences were noted forthe Topical Diclofenac Solution or control (Retin-A) treated animals ofgroups 1 and 4, respectively, for C_(max) and AUC-values of test day 1compared to test days 21, 28 and 35.

Conclusions:

Epicutaneous application of Topical Diclofenac Solution four times dailyfrom test day 6 to 20 with a single dose applied on the morning of day21, while resulting in relevant systemic exposure to diclofenac, did notinduce relevant local or systemic untoward changes. Treatment withTopical Diclofenac Solution, however, did not amplify the exposure ofoxybenzone, an epicutaneously applied toxin.

That systemic diclofenac steady state was reached by day 19 indicatesthat a maximum degree of skin permeabilization for diclofenac by theTopical Diclofenac Solution vehicle has been reached after 14 days oftreatment with Topical Diclofenac Solution.

Results also showed that there was no quantifiable systemic absorptionof DEET or 2,4-D at baseline (prior to treatment with Topical DiclofenacSolution or Rogaine) or following a 15-day pre-treatment with TopicalDiclofenac Solution or Rogaine (Treatment Groups 2, 3, 5 and 6).

According to the results, systemic absorption of oxybenzone occurredprior to treatment with Topical Diclofenac Solution and Retin-A control(days 1-3) and this level thus represents baseline systemic absorptionof oxybenzone. There was no significant difference in baselineoxybenzone systemic levels and systemic levels obtained following a 14day pre-treatment period with Topical Diclofenac Solution and it istherefore concluded Topical Diclofenac Solution did not enhance thesystemic absorption of oxybenzone. However, there was a significantdifference in baseline oxybenzone systemic levels and systemic levelsobtained following a 14 day pre-treatment period with Retin-A Control.Therefore, Retin-A enhances the systemic absorption of oxybenzone.

It can be concluded that a 15-day repeat dose treatment with TopicalDiclofenac Solution, QID, while resulting in a maximum degree of skinpermeabilization for diclofenac, does not enhance the systemicabsorption of oxybenzone.

Example 3 Influence of a Topical Diclofenac Solution on PercutaneousAbsorption of Two Different Environmental Toxins after RepeatedEpicutaneous Administration to Minipigs

This Example describes novel preclinical information that may, forexample, be provided to a user according to the present invention, whichrelates to the influence of a topical diclofenac preparation containing1.5% diclofenac sodium (2-[(2,6-dichlorophenyl) amino] benzeneaceticacid, monosodium salt), 45.5% DMSO, ethanol, propylene glycol,glycerine, and water (“Topical Diclofenac Solution”) on the percutaneousabsorption of two environmental toxins from Example 2, evaluated athigher doses in a study involving repeated epicutaneous administrationto minipigs. In Example 2 the dose levels for the toxins were selectedbased on the available human environmental and occupational exposuredata but the results did not provide systemic exposure above the limitof quantitation. Thus, to increase the potential systemic exposure ofthe toxin, the maximum dermal exposure to the toxin was selected forthis study. As in Example 2, the Test Item was Topical DiclofenacSolution.

The two environmental toxins DEET, i.e., N,N-diethyl-m-toluamide (in theform of Deep woods OFF!® pump spray; active compound 25%N,N-diethyl-m-toluamide) and 2,4-D, i.e., 2,4-D, dimethylamine salt (inthe form of Spectracide Weed Stop 2× For Lawns Concentrate; activecompound 7.57% 2,4-D, dimethylamine salt). The single Control Item usedin the study was Retin-A 0.1% (tretinoin) cream.

Methods:

The study was carried out as described in Example 2 using 12 minipigs(four groups of three female minipigs each). Animals of groups 1 and 2were treated with the Test Item from the morning of day 6 until themorning of day 21; groups 3 and 4 were treated with Retin-A 0.1% (theControl Item) from the evening of day 6 until the evening of day 20.

Single doses of the toxins were administered on the morning of days 1,21, 28, and 35. Groups no. 1 (Test Item) and 3 (Control Item) wereinvestigated with Toxin no. 1 (DEET), whereas the animals of groups 2(Test item) and 4 (Control Item) were investigated with Toxin no. 2(2,4-D). The volume of the toxin formulation applied was 1 mL on day 1and 1.5 mL on subsequent doses starting on day 21. In contrast toExample 2, the 1.5 mL toxin volume resulted in an administered dose ofDEET (Toxin No. 1) of 375,000 μg and an administered dose of 2,4-D(Toxin No. 2) of 113,550 μg.

The Test Item, Control Item and Toxins were administered as follows. TheTest Item was administered four times daily from test days 6 to 20(7:30, 12:30, 17:30, 22:30); one single dose on day 21 (7:30). TheControl Item was administered once daily from test days 6 to 20 (22:30).Toxin Nos. 1 and 2 were administered once on test day 1 (beforeadministration of the Test Item or the Controls) and once on test days21 (after administration of the Test Item), 28 and 35.

Results:

Exposure to DEET could be well-quantified on all application days. Inthe Topical Diclofenac Solution arm, the dose-normalized area exposureto DEET (AUC₀₋₄₈) on days 21, 28, and 35 was on average 1.18, 1.61, and1.44 times higher than on day 1, respectively; but was not statisticallysignificantly different. Under the Retin-A Control treatment, the dosenormalized area exposure on these days was on average 1.56, 1.83, and1.30 times higher than on day 1 and were statistically significantlydifferent on test day 28.

Exposure to 2,4-D could be well-quantified on all application days.Under the Test treatment, the dose normalized area exposure to 2,4-D ondays 21, 28, and 35 was on average 2.04, 1.27, and 1.16 times lower thanon day 1, respectively, but was not statistically significantlydifferent. Under the Control treatment, the dose normalized areaexposure on these days was on average 10.84, 8.86, and 7.29 times higherthan on day 1 and were statistically significantly different.Accordingly, there is a distinct amplification of the 2,4-D exposure inthe control group (Retin-A), but not in the animals treated with theTest treatment (Topical Diclofenac Solution).

No signs of local intolerance reactions were observed for any of theminipigs after repeated epicutaneous administration of 0.22 mL TopicalDiclofenac Solution/animal (approx. 3.5 mg diclofenac sodium/animal) andToxin No. 1. Animal no. 4 (group 2) treated with 0.22 mL TopicalDiclofenac Solution/animal (approx. 3.5 mg diclofenac sodium/animal) andToxin No. 2 revealed a very slight to well defined erythema on test days7 to 14. Animal nos. 7 and 8 (group 3) treated with 112.5 mg Retin-A0.1% (tretinoin) cream/animal and Toxin No. 1 revealed a well definederythema on test days 21 and 22 and a very slight to well definederythema on test day 35. Animal no. 12 (group 4) treated with 112.5 mgRetin-A 0.1% (tretinoin) cream/animal and toxin no. 2 (group 4) revealeda moderate to severe erythema on test day 21 and a well defined erythemaon test day 35.

No signs of systemic intolerance were noted for any of the minipigsafter repeated epicutaneous administration of either 0.22 mL TopicalDiclofenac Solution/animal (approx. 3.5 mg diclofenac sodium/animal) orthe Control Item and the two toxins. Additionally, none of the animalsdied prematurely; the body weight was in the normal range in all animalsthroughout the course of the study; and no influence was noted on thefood and drinking water consumption for any of the animals.

Epicutaneous application of Topical Diclofenac Solution four times dailyfrom test day 6 to 20 with a single dose applied on the morning of day21 resulted in relevant systemic exposure to diclofenac.

Conclusions:

Epicutaneous application of Topical Diclofenac Solution four times dailyfrom test day 6 to 20 with a single dose applied on the morning of day21, while resulting in relevant systemic exposure to diclofenac, did notinduce relevant local or systemic untoward changes. The achievement ofsteady state levels of diclofenac by day 21 indicates that that amaximum degree of skin permeabilization for diclofenac had been reached.In contrast to Retin-A, treatment with Topical Diclofenac Solution didnot amplify the toxic risk of epicutaneously applied toxins such as2,4-D and DEET.

Example 4 Effect on Stratum Corneum Barrier Function of Multiple Dosesof Topical Diclofenac Solution as Measured by Transepidermal Water-Loss

This Example describes novel preclinical information that may, forexample, be provided to a user according to the present invention, whichcomprise information regarding an assessment of the effect on stratumcorneum barrier function, as measured by transepidermal water loss(“TEWL”), of multiple doses of a topical diclofenac preparationcontaining 1.5% diclofenac sodium (2-[(2,6-dichlorophenyl) amino]benzeneacetic acid, monosodium salt), 45.5% DMSO, ethanol, propyleneglycol, glycerine, and water (“Topical Diclofenac Solution”) comparedwith a positive control, Retin-A®, and an untreated site as a negativecontrol.

Study Design:

The study was conducted as a four-period, open label, paired comparisonin a single group. Period One (Baseline) was a period of one week priorto the first application on Day 1. At Period Two (Treatment), subjectsapplied test articles (Topical Diclofenac Solution or Retin-A®) for aperiod of six weeks. At Period Three (Recovery), subjects underwent arecovery period of two weeks following the treatment period. At PeriodFour (Retin-A® Challenge) subjects applied Retin-A® under occlusion tothe same test site as during Period Two for a period of up to two weeks.Thus, the total study duration was approximately 12 weeks, with eighttreatment weeks spread between Period Two (six-week treatment period)and Period Four (two-week treatment period).

Protocol:

At Period One (Baseline), baseline measurements of TEWL were performedon Days −7, −5, and −3 prior to the first application on Day 1. AtPeriod Two (Treatment), subjects applied test articles for a period ofsix weeks. TEWL was measured on each of the test sites (4 cm×4 cm)immediately before application of the morning dose of test articles onDays 1, 3, 5, 8, 15, 22, 29, 36 and 43. Each subject applied one drop(approximately 30 μL) of Topical Diclofenac Solution to a test site onthe right or left volar forearm (as randomized) four times a day for sixweeks, at approximately 08:00, 13:00, 18:00 and 23:00 hours. The dose ofTopical Diclofenac Solution utilized in this study (approximately 30 μLto a surface area of 16 cm²) was calculated to approximate the TopicalDiclofenac Solution dose that applied QID to the knee is shown inExample 1 to be effective for treatment of the pain and symptoms of kneeosteoarthritis, namely 40 drops (approximately 1.2 mL) to a knee surfacearea of approximately 800 cm². Each subject applied a dab (about 12 mg)of Retin-A® to a separate test site on the opposite volar forearm onceper day for six weeks, at approximately 08:00 hours. The subject usedhis/her finger to spread the test articles over their respective testsites. Each forearm had a test area that was left untreated as anegative control. The subjects allowed the test articles to dry beforecovering the test sites with clothing and avoided sunlight exposure tothe test sites during the study. At Period Three (Recovery), subjectsunderwent a recovery period of two weeks following the treatment period.TEWL was measured on each of the test sites on the morning of Days 45,47, 50, and 58. At Period Four (Retin-A® Challenge) on Days 58-71,Retin-A® was applied under occlusion to the same test site to whichRetin-A® had been applied during Period Two. A designated member of thestudy staff applied two dabs (about 24 mg) of Retin-A® to the Retin-A®test site, once daily for 14 days, at approximately 08:00 hours. TheRetin-A® test site was occluded using polyethylene film (Saran Wrap®)for 15 hours following each application. TEWL was measured on theRetin-A® site and the untreated control site of the same arm on themorning of Days 59-72.

TEWL:

TEWL analysis was carried out on the data of the intent-to-treat (“ITT”)analysis group. The ITT analysis group included all enrolled subjectswho received at least one dose of test article. TEWL was quantifiedusing a VapoMeter, a closed chamber evaporimeter. Change in TEWL betweenthe treated and untreated sites was monitored over time. Descriptivestatistics (arithmetic mean, standard deviation, coefficient ofvariation, median, minimum, and maximum) for the TEWL data wassummarized for each treatment. Individual and mean TEWL time profileswere plotted by treatment and period on a linear scale.

To assess the validity of the study to measure changes in TEWL, thepost-treatment results for the positive control, Retin-A®, were comparedto the untreated site on the same arm using repeated measures analysisof covariance (“ANCOVA”) with the average pre-treatment TEWL measure asthe covariate. During conduct of the study and preliminary review of thedata, it appeared that the positive control was not causing skinirritation to the expected degree. In order to validate the study, aRetin-A® Challenge Period was added via a protocol amendment asdescribed above, and the ANCOVA analysis was repeated for the ChallengePeriod using Day 58 TEWL measure as the baseline covariate. The TEWLresponse for the Topical Diclofenac Solution site during the TreatmentPeriod was compared to the untreated site on the same arm using repeatedmeasures ANCOVA with the average pre-treatment TEWL measure as thecovariate. Secondary analyses included comparisons between TopicalDiclofenac Solution and Retin-A® change in TEWL (difference fromuntreated site) for the Treatment Period, and correlation analysesbetween TEWL and the variables: skin irritation score, temperature andhumidity.

Safety:

Safety was assessed through evaluation of the safety variables: adverseevents, skin irritation score, laboratory analysis and vital signs.Safety analysis was carried out on the data of every subject whoreceived at least one treatment with study article.

TEWL Results:

The results for treatment with Topical Diclofenac Solution indicate thatit did not cause an increase in TEWL relative to the untreated sitefollowing 6 weeks of treatment at a dose, that applied QID to the knee,is shown in Example 1 to be effective for treatment of the pain andsymptoms of knee osteoarthritis. No difference between TopicalDiclofenac Solution and Retin-A® was noted during the Treatment Period(neither caused an increase in TEWL during this period of the study).

During the Challenge Period with Retin-A®, skin irritation was noted(see Safety Results) and a significant increase in TEWL relative to theuntreated site was observed. These results for the Challenge Periodvalidate the study design by showing that the subjects were responsiveto this positive control, a known skin irritant.

Mean TEWL time profiles are shown in FIG. 1 (Retin-A®) and FIG. 2(Topical Diclofenac Solution). Review of FIG. 1 shows an increase inTEWL for the Retin-A® treated site during the Challenge Period relativeto the untreated site, and no difference between treated and untreatedsites for Topical Diclofenac Solution and Retin-A® during the TreatmentPeriod.

Safety Results:

There were a total of 51 adverse events reported by 12 subjects. Themajority of adverse events were classified as mild in severity (35events) and classified as probably related to the test article (32events). The majority of the adverse events reported consisted of skinirritation responses (i.e. contact dermatitis, dry skin, pruritus).These were observed at the Retin-A® application test sites for allsubjects except for one who reported the adverse event ‘dry skin’ thatoccurred at the Topical Diclofenac Solution treated test site.

The frequency of worst skin irritation score during the Treatment Periodfor Topical Diclofenac Solution revealed 14 of 15 subjects with a worstscore of zero, indicating no skin irritation. One subject had a score of0.5 (dryness or flaking) for the Topical Diclofenac Solution treatedsite. For Retin-A®, no skin irritation was observed during the Treatmentand Recovery Periods. During the Challenge Period, 7 subjects had aworst score of 3 (erythema with induration and vesiculation) and onesubject had a score of 1 (erythema) for the Retin-A® treated site. Theoccurrence of skin irritation for the Retin-A® sites was expected forthis positive control.

Two subjects experienced changes in clinical laboratory evaluations(glucose, ALT and AST elevations) that were documented as adverseevents. All three adverse events were considered mild and not related tothe test articles.

There were no clinically significant findings related to blood pressure,pulse or respiration rates.

Conclusions:

The objective of this study was to evaluate the effect on stratumcorneum barrier function, as measured by TEWL, of chronic application ofTopical Diclofenac Solution as compared with a positive control,Retin-A®, and an untreated site as a negative control.

The dose of Topical Diclofenac Solution utilized in this study(approximately 30 μL to a surface area of 16 cm²) was calculated toapproximate that shown in Example 1 to be effective for treatment of thepain and symptoms of knee osteoarthritis when applied QID to the knee(40 drops (approximately 1.2 mL) to a knee surface area of approximately800 cm²). Following chronic dosing with Topical Diclofenac Solution for6 weeks in this study, no significant increase in TEWL was observed. Asmeasurement of TEWL has been shown to be a validated method forassessing skin barrier function (Fluhr J W, Feingold K R, Elias P M.Transepidermal water loss reflects permeability status: validation inhuman and rodent in vivo and ex vivo models. Exp Dermatol 2006;15:483-492), these results indicate that Topical Diclofenac Solution didnot alter the stratum corneum barrier function.

Treatment with Retin-A®, used as a positive control in this study, inthe Challenge Period confirmed skin irritation following Retin-A®treatment and a resulting increase in TEWL, thus validating the study.

In conclusion, the results of this study demonstrate that followingchronic dosing with Topical Diclofenac Solution, no significant increasein TEWL was observed, indicating that Topical Diclofenac Solution didnot substantially alter the stratum corneum barrier function.

Example 5 Ophthalmologic Effects of Topically Applied DMSO in a 52-WeekNon-Occluded Dermal Toxicity Study in Göttingen Minipigs

This Example describes novel preclinical information that may, forexample, be provided to a user according to the present invention,comprising the results of a study that was conducted on minipigs whichprovides information about the ocular safety profile of dermally appliedformulations containing purified DMSO.

The broad aim of the study was to evaluate the potential dermal toxicityof DMSO when administered topically to four groups of GöttingenMinipigs® for 52 weeks at concentrations of 0, 9%, 45.5% and 90% (w/w)and to evaluate reversibility, progression, or delayed appearance of anyobserved changes following a 1-month postdose observation period. Twoadditional groups of Göttingen Minipigs® were dosed topically for 39weeks at 0% and 90% followed by a 4-month recovery post dose observationperiod.

Four groups consisting of six animals/sex/group received DMSO atrespective dose levels of 0, 9, 45.5, or 90% (w/w) by dermal applicationthree times a day for 364 consecutive days. Following 52 weeks ofadministration, two animals/sex at 0, 9, 45.5, and 90% dose levels weremaintained for a 4-week recovery period. Two additional groupsconsisting of six animals/sex/group received the control or 90% (w/w)DMSO by dermal application three times a day for 273 consecutive days.Following 39 weeks of administration, two animals/sex at 0 and 90% doselevels were maintained for a 4 month recovery period. The control ortest article was administered to all groups at a dose volume of 4.5mL/dose/application site (0.015 mL/cm²; 300 cm² application site) untilWeek 20. Beginning Week 20 the control or test article was administeredto all groups at a dose volume 5.6 mL/dose/application site (0.015mL/cm²; 375 cm² application site).

Group Assignments Group Dose Number of Animals Number Concentration (%)Male Female 1^(a) 0 6 6 2^(a) 9 6 6 3^(a) 45.5 6 6 4^(a) 90 6 6 5^(b) 06 6 6^(b) 90 6 6 ^(a)Four animals/sex/group were necropsied after 52weeks of administration. Two animals/sex/group remained on study for a4-week recovery period. ^(b)Four animals/sex/group were necropsied after39 weeks of administration. Two animals/sex/group remained on study fora 4-month recovery period.

Compositions of the control and test articles were as follows

Control Vehicle

Ethanol (95% v/v) 11.79% w/w Propylene Glycol 11.20% w/w Glycerin 11.20%w/w Purified Water 65.81% w/w

9% DMSO

Ethanol (95% v/v) 11.79% w/w Propylene Glycol 11.20% w/w Glycerin 11.20%w/w DMSO 9.00% w/w Purified Water 56.81% w/w

45.5% DMSO

Ethanol (95% v/v) 11.79% w/w Propylene Glycol 11.20% w/w Glycerin 11.20%w/w DMSO 45.50% w/w Purified Water 20.31% w/w

90% DMSO

Ethanol (95% v/v) 2.00% w/w Propylene Glycol 2.00% w/w Glycerin 2.00%w/w DMSO 90.00% w/w Purified Water 4.00% w/w

Observations for morbidity, mortality, injury, and the availability offood and water were conducted twice daily for all animals. Clinicalobservations were conducted weekly. At the end of the each treatment andrecovery period, necropsy examinations were performed, organ weightswere recorded, and selected tissues were microscopically examined.

One female at 90% DMSO was euthanized in extremis on Day 151 of thestudy. The cause of the morbidity of this animal was determined to berespiratory distress and this was considered incidental to treatment andnot test article-related. All remaining animals survived to theirscheduled termination at the terminal necropsy at 39 or 52 weeks and the4-week and 4-month recovery periods.

Ophthalmoscopic examinations were conducted pretest, and during Weeks26, 39, and 52. Examinations were performed by a doctor of veterinarymedicine with Diplomate, American College of Veterinary Ophthalmologistscredentials.

Unexpectedly given the results of earlier studies on non-primatespecies, no increased risk for development of lens opacities orrefractive index changes associated with DMSO were observed. In fact, notest article-related ophthalmoscopic abnormalities of any kind weredetected during the study. One female in the control group (i.e. ananimal that had not been exposed to DMSO) had a posterior cortical axialcataract with equatorial extrusion at the Week 39 ophthalmoscopicexamination. One male at 45.5% DMSO, one male at 90% DMSO, and onecontrol female had conjunctivitis in one or both eyes only at thepretest examination. No other abnormalities were detected in any male orfemale at any of the ophthalmoscopic examinations.

Example 6 Ophthalmologic Effects of DMSO in a 26-Week Dermal ToxicityStudy in Sprague-Dawley Rats Followed by a 12-Week Recovery Period

This Example describes novel preclinical information that may, forexample, be provided to a user according to the present invention,comprising the results of a study conducted to evaluate the toxicity oftest articles containing DMSO after dermal administration for 26 weeks,three times per day, and to evaluate reversibility of any observedchanges following a 12-week post-dose observation period. Threetreatment groups of 25 male and 25 female CD® [Crl:CD®(SD)]Sprague-Dawley rats were administered the test article, Dimethylsulfoxide (DMSO), at respective dose concentrations of 9, 45.5, and 90%w/w. One additional group of 25 animals/sex served as the control andreceived the vehicle. Compositions of the test articles and control wereidentical to those used in Example 5 above. The vehicle or test articlewas administered to all groups epicutaneously, three times a day for 182consecutive days, at a dose volume of 0.65 mL. Prior to test articleadministration, the hair was clipped from the back of the animalcomprising no less than 10% of the total body surface area as estimatedusing the equation A=9.6*W^(2/3) where A was the estimated total bodysurface in square centimeters and W was the body weight in grams. Thearea was adjusted weekly by group based on the mean body weight for eachsex. Following 182 days of administration, 5 animals/sex/group weremaintained for a 12-week recovery period.

Observations for morbidity, mortality, injury, and the availability offood and water were conducted twice daily for all animals.Ophthalmoscopic examinations were conducted pretest on all animals andprior to the terminal and recovery necropsies on all main study animalsby doctors of veterinary medicine with Diplomate, American College ofVeterinary Ophthalmologists credentials.

One female at 9% DMSO (Low dose), two males and one female at 90% DMSO(High dose) died, and two females at 45.5% DMSO (Mid dose), and onefemale at 90% DMSO were euthanized in extremis during the study. None ofthese deaths were considered to be related to treatment.

No test article-related ophthalmoscopic abnormalities were detected inany animal during the pretest, terminal, and recovery ophthalmoscopicexaminations. At the recovery ophthalmoscopic examination, one female at45.5% DMSO was seen with superficial keratitis in both eyes. Thisisolated common finding was considered incidental to treatment.

Example 7 A Single-Dose Pharmacokinetic Evaluation of a Topical SolutionContaining 1.5% w/w Diclofenac Sodium and 45.5% DMSO in Normal HealthyNon-Smoking Male and Female Subjects

This Example describes novel clinical information that may, for example,be provided to a user according to the present invention, comprising theresults of study conducted to evaluate the pharmacokinetics ofdiclofenac sodium, dimethyl sulfoxide (DMSO) and dimethyl sulfone (themajor metabolite of DMSO) after a single-dose application of a topicaldiclofenac preparation containing 1.5% diclofenac sodium(2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt),45.5% DMSO, ethanol, propylene glycol, glycerine, and water (“TopicalDiclofenac Solution” [Pennsaid® (Nuvo Research Inc, Mississauga, OntarioCanada]). The study followed a one-period, open-label, single-dosedesign in 18 normal, healthy, non-smoking male and female subjects inwhich Topical Diclofenac Solution was applied to both knees of eachsubject in the study.

The 18 subjects enrolled in the study consisted of 14 Caucasians, 1Asian and 3 Blacks (9 males, 9 females) with a mean age of 33 years(range=22 to 46 years). The subjects' mean height was 174 cm (range=163to 188 cm) and the mean weight was 75 kg (range=54 to 90 kg).

Each subject was instructed to apply Topical Diclofenac Solution toclean knees, total 40 drops per knee: 10 drops each to the front of theknee, to each side and to the back. To avoid spillage, the subject wasinstructed to apply and spread 5 drops at a time, directly onto his/herhand, and then onto the site. The application left the area visibly wetfor several minutes and was applied without massaging. TopicalDiclofenac Solution was applied to both knees; the order of applicationdid not matter. After each dosing, subjects waited for the applicationsite to dry prior to dressing. The subject washed his/her hands aftercomplete application to both knees.

The subjects fasted overnight for at least ten hours prior to TopicalDiclofenac Solution administration and at least four hours followingdosing. The treatments were administered topically to both knees in eachsubject starting at 7:00 a.m. (0.0 hour), with three-minute intervalsbetween subjects.

Subjects were informed not to take any prescription medication, otherthan hormonal contraceptives, from at least 14 days prior to the studyuntil the end of the study. Subjects were also advised not to take anyover-the-counter drugs, except for spermicidal barrier contraceptiveproducts, for at least seven days prior to the study up until the end ofthe study. They were specifically reminded that this included coldpreparations, Aspirin®, Bufferin®, Excedrin®, Anacin®, etc.,herbal/natural supplements, vitamins and antacid (magnesium and aluminumhydroxide) preparations. Subjects were informed that concomitantmedication, whether prescription or over-the-counter, was not permittedduring the study. Subjects were requested to abstain from grapefruitproducts, xanthine- and caffeine-containing foods and beverages (thisincluded tea, coffee, chocolate and cola drinks) for 24 hours prior tothe start of the study and until after the final blood draws for thestudy. Subjects were also requested to abstain from alcohol products for48 hours prior to the start of the study and until after the final blooddraws of the study.

Blood samples were collected at 0.0 hour (pre-dose), 1.0, 2.0, 4.0, 6.0,8.0, 10.0, 12.0, 24.0, 36.0, 48.0, 60.0, 72.0, 96.0, 120.0, 144.0,168.0, 192.0, 216.0 and 240.0 (hours post-dose).

The blood samples were kept in an ice bath prior to centrifugation andwere centrifuged as soon as possible (within 30 minutes) underrefrigerated conditions at 3,500 rpm for seven minutes. The plasma wasremoved from each blood collection tube and aliquotted into pre-cooled,labeled, duplicate, polypropylene tubes, kept in an ice bath prior tobeing flash frozen in an upright position, in a dry-ice acetone bath andstored frozen at minus (−) 70° C.±10° C. The tubes were labeled with thestudy number, dosing period, subject number, study period, sampling timepoint, aliquot/tube number and matrix. Upon completion of the clinicalportion of the study, all samples were transported in dry-ice to ananalytical laboratory (Maxxam Analytics Inc.) for the analysis ofdiclofenac sodium, dimethyl sulfoxide and dimethyl sulfone usingvalidated analytical methods.

Dimethyl sulfone was below the limit of quantitation in most samples andtherefore pharmacokinetic analysis was not conducted. Graphs showing theaverage measured diclofenac sodium concentration and DMSO concentrationin the subjects as a function of time are provided in FIGS. 3 and 4.

Pharmacokinetic analysis of the data was conducted using WinNonlinversion 4.0 (Pharsight, Carry, US). The principal statistical softwareused was SAS®, version 8.00 (Statistical Analysis System). Results forpharmacokinetic parameters are summarized in the following tables.

PENNSAID ® TOPICAL SOLUTION Pharmacokinetic n = 18 Parameter Mean ± SDAUC_(0-t)(ng · hr/mL) 177.51 ± 72.62 AUC_(0-inf) (ng · hr/mL)† 196.27 ±68.47 C_(max) (ng/mL)  8.05 ± 5.94 T_(max) (hr) 11.01 ± 6.44 t_(1/2)(hr)†  36.72 ± 20.82 K_(el) (hr⁻¹)†  0.024 ± 0.0098 CL/F (L/hr)† 244.66± 84.72 †n = 13

Single-Dose Pharmacokinetic Parameters for Diclofenac Sodium (for TwoKnee Application)

PENNSAID ® TOPICAL SOLUTION Pharmacokinetic n = 18 Parameter Mean ± SDAUC_(0-t) (μg · hr/mL) 8.719 ± 4.611 AUC_(0-inf) (μg · hr/mL)† 9.174 ±3.751 C_(max) (μg/mL) 0.475 ± 0.335 T_(max) (hr) 8.451 ± 2.708 t_(1/2)(hr)† 8.422 ± 7.307 K_(el) (hr⁻¹)† 0.1136 ± 0.0470 CL/F (L/hr)† 163.49 ±64.14  †n = 9

Single-Dose Pharmacokinetic Parameters for Dimethyl Sulfoxide (for TwoKnee Application)

Meanings of each of the parameters in the tables above are as follows:

-   -   AUC_(0-t) Area under the concentration-time curve from time zero        to time of last sampling time point    -   AUC_(0-inf) Area under the concentration-time curve from time        zero to infinity    -   C_(max) Maximum plasma concentration after dosing    -   T_(max) Time to occurrence of Cmax    -   t_(1/2) Apparent elimination half-life    -   K_(el) Apparent elimination rate constant    -   CL/F Apparent total body clearance

Example 8 A Multi-Dose Pharmacokinetic Evaluation of a Topical SolutionContaining 1.5% w/w Diclofenac Sodium and 45.5% DMSO in Normal HealthyNon-Smoking Male and Female Subjects

This Example describes novel clinical information that may, for example,be provided to a user according to the present invention, comprising theresults of a study conducted to evaluate the pharmacokinetics ofdiclofenac sodium, dimethyl sulfoxide and dimethyl sulfone aftermultiple doses of a topical diclofenac preparation containing 1.5%diclofenac sodium (2-[(2,6-dichlorophenyl) amino] benzeneacetic acid,monosodium salt), 45.5% DMSO, ethanol, propylene glycol, glycerine, andwater (“Topical Diclofenac Solution” [Pennsaid® (Nuvo Research Inc,Mississauga, Ontario Canada]) which, as in the previous Example 7, wasapplied to both knees of each subject. This study followed a one-period,open-label, multiple-dose design in 20 normal healthy, non-smoking maleand female subjects.

Twenty subjects (10 males, 10 females) with a mean age of 33 years(range=18 to 43 years) were enrolled in this study. The subjects' meanheight was 171 cm (range=157 to 185 cm) and their mean weight was 69 kg(range=48 to 87 kg). The subjects consisted of 15 Caucasians, 3 Asiansand 2 Blacks.

The treatment (40 drops, applied on the knee four times a day) wascarried on for 7 days, and the pharmacokinetic profile was characterizedon Day 8 after the 29th administration. Each dose of Topical DiclofenacSolution was applied to the knee following the procedure describedpreviously in Example 7.

Doses were applied either at a clinic or at home according to followingschedule:

Days 1 and 6: The subjects applied the first dose of Topical DiclofenacSolution to both knees in the clinic under supervision. The subjectsapplied the second, third and fourth doses of Topical DiclofenacSolution at home.

Days 2 to 5: The subjects applied all four doses of Topical DiclofenacSolution at home.

Day 7: The subjects applied the first dose of Topical DiclofenacSolution in the clinic and then exited. The second and third doses wereapplied at home. The fourth dose was applied in the clinic.

Day 8: The subjects applied the last dose of Topical Diclofenac Solutionto both knees in the clinic following an overnight fast of at least tenhours.

Blood samples were drawn according to the following:

Days 1 and Day 6: 0.0 hour (pre-dose).

Day 7: 0.0 hour (pre-dose).

Day 8: 0.0 hour (pre-dose), 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 24.0, 36.0,48.0, 60.0, 72.0, 96.0, 120.0, 168.0, 216.0, 264.0, 312.0 and 360.0hours post 0.0 hour post-drug administration Day 8.

Blood samples were processed and analyzed using the methods describedpreviously in Example 7.

One subject dropped out of the study for personal reasons so plasmaconcentration data from the 19 subjects who received the TopicalDiclofenac Solution and who completed the study period were used in thepharmacokinetic analyses.

Steady state was achieved on Day 6 (after 20 doses) for the 3 molecularentities analyzed. On Day 8, diclofenac sodium remained measurable up to360 hours post-dose in 11 subjects. On Day 8, DMSO and dimethyl sulfone(“DMSO₂”) remained measurable up to 120 hours (10 subjects) and 216hours (9 subjects) post-dose, respectively.

Plots of Diclofenac, DMSO and DMSO₂ concentrations are provided in FIGS.5-7.

The pharmacokinetic analysis was conducted using WinNonlin Version 4.0(Pharsight, Carry, US). The principal statistical software used wasSAS®, version 8.00. Results for important pharmacokinetic parameters areprovided in the tables below.

PENNSAID ® TOPICAL SOLUTION Pharmacokinetic n = 19 Parameter Mean ± SDAUC_(0-t) (ng · hr/mL) 695.398 ± 348.866 AUC_(0-inf) (ng · hr/mL)†745.192 ± 374.740 C_(max) (ng/mL) 19.415 ± 9.326  T_(max) (hr) 4.005 ±6.541 t_(1/2) (hr)† 78.972 ± 38.133 K_(el) (hr⁻¹)† 0.0105 ± 0.0040 †n =15

Multiple-Dose Pharmacokinetic Parameters for Diclofenac Sodium (forTwo-Knee Application)

PENNSAID ® TOPICAL SOLUTION Pharmacokinetic n = 19 Parameter Mean ± SDAUC_(0-t) (ug · hr/mL) 31.887 ± 15.520 AUC_(0-inf) (ug · hr/mL)† 35.979± 15.419 C_(max) (ug/mL) 1.206 ± 0.575 T_(max) (hr) 3.842 ± 3.468t_(1/2) (hr)† 43.123 ± 22.968 K_(el) (hr⁻¹)† 0.0213 ± 0.0124 †n = 13

Multiple-Dose Pharmacokinetic Parameters for Dimethyl Sulfoxide (forTwo-Knee Application)

PENNSAID ® TOPICAL SOLUTION Pharmacokinetic n = 19 Parameter Mean ± SDAUC_(0-t) (ug · hr/mL) 1525.292 ± 1065.245 AUC_(0-inf) (ug · hr/mL)†2339.190 ± 1276.555 C_(max) (ug/mL) 18.033 ± 10.587 T_(max) (hr)  9.397± 13.341 t_(1/2) (hr)† 61.287 ± 18.376 K_(el) (hr⁻¹)† 0.0123 ± 0.0039 †n= 11

Multiple-Dose Pharmacokinetic Parameters for Dimethyl Sulfone (forTwo-Knee Application)

Quantities reported in the above tables have the meanings providedpreviously in Example 7. Origin of time (t=0) for calculation ofAUC_(0-t) and AUC_(0-inf) is time of the last dose of drug on Day 8.

It will be appreciated that the data provided in Examples 7 and 8evidence that the systemic exposure to diclofenac caused by use ofTopical Diclofenac Solution to treat osteoarthritis of the knee (40drops per knee QID) is much lower than that caused by a typical oraldose of diclofenac used in treatment of osteoarthritis (e.g. 50 mg TID).For example the label of Voltaren® Gel(http://www.voltarengel.com/pdf/Voltaren-PI-10-19.pdf) reports meanAUC₀₋₂₄=3890 ng·h/mL and mean C_(max) of 2270 ng/mL for subjects taking50 mg of oral diclofenac TID. Assuming the effects of additional dosesof Topical Diclofenac Solution are additive, one would conclude from theAUC_(0-inf) provided in Example 7 that the Topical Diclofenac Solutionosteoarthritis dose results in only about 20% of the systemic exposureto the active provided by the oral drug. The fact that TopicalDiclofenac Solution is shown to be comparable in efficacy to oraldiclofenac sodium for treatment of osteoarthritis (see Example 1) isvery surprising in view of these facts, especially as it is widelybelieved that NSAIDs, such as diclofenac, exert their analgesic effectsboth locally and centrally. Using the data from Example 8 it also can becomputed that C_(max) of orally administered diclofenac is more than onehundred fold higher than C_(max) for Topical Diclofenac Solution.

Example 9 Assessment of Drying Time Following Application of a TopicalFormulation Containing Diclofenac Sodium to Normal Subjects

The objective of this study was to assess the drying time of a topicaldiclofenac solution containing 1.5% diclofenac sodium, 45.5% DMSO,ethanol, propylene glycol, glycerine, and water (“Topical DiclofenacSolution”) when applied topically to the skin surface of the kneefollowing a single dose application.

Using a pre-designed template, the knee application area (100 cm²centered just above the patella) was outlined in ink (the choice of kneewas assigned by randomization). Each subject received an applied dose,0.15 mL, of Topical Diclofenac Solution to the 100 cm² area on his/herknee and spread the test article using his/her fingers to completelycover the application area just up to the margin of the demarcation(this amount of drug product corresponding to a typical areal dose ofTopical Diclofenac Solution used in the treatment of osteoarthritis ofthe knee). The applied dose remained un-occluded throughout the studyduration.

Visual and blotted assessments were made at pre-dose, immediatelyfollowing dose application (approximately 2 minutes post-dose) and at 5,10, 15, 20, 30, 60, 120, and 240 minutes after dose application to thetreated knee. Assessments were conducted on 9 separate 3 cm×3 cm testsites within the 100 cm² dosed area. The pre-dose assessment wasperformed on the test site in the center of the dosed area. The 9post-dose assessments were conducted on the 9 test sites, in sequencestarting at one corner. Only one test site was assessed for eachpost-dose assessment time point.

Four parameters were defined in the protocol to assess drying time.These included the weight of the tissue/vial combination, VisualAppearance Score, Visual Adhesion Score and Visual Adsorption Score asexplained further below.

The visual examination of the test sites was scored using the scalebelow.

Visual Appearance Score:

1. Wet, shiny with a clear look of physical solution being present,

2. Damp, shiny, visible film with no visible solution present,

3. Damp, matte appearance, visible film,

4. Dry, matte appearance, visible film,

5. Dry, no visible film

Following the visual assessment, the dosed site was tested foradsorption or adherence to a 3 cm×3 cm square laboratory tissue (e.g.KimWipes). Using forceps, the tissue was removed from a sealed,previously weighed vial and gently placed onto the test site. After fiveseconds, the tissue was removed using forceps by one corner whilemonitoring its adhesion to the site. Adherence of the tissue to the testsite was scored using the scale below.

Visual Adhesion Score:

1. Distinct adhesion to the full test site,

2. Light to moderate adhesion to all or a portion of the test site,

3. No adhesion to the test site.

The tissue was visually inspected for fluid adsorption to the tissue andthe adsorption was scored using the scale below.

Visual Adsorption Score:

1. Demonstrates fluid adsorption to the tissue to the size of the testarea,

2. Demonstrates fluid adsorption to the tissue to a size less than thetest area,

3. Demonstrates no fluid adsorption to the tissue.

The tissue was placed back into its labeled vial and the vial was sealedto prevent evaporation. Within 2 hours of collection the vial wasre-weighed and the weight recorded.

A total of 12 healthy adult male and female subjects participated in thestudy. The study was successfully completed by all 12 subjects enrolled.Data for these subjects were used in the statistical analysis, exceptwhere one subject was removed as a statistical outlier.

The results of this study indicate that dryness occurred as early as 10minutes post-dose in most subjects, as shown by visual appearance ofdryness (7/11 subjects), no adhesion of the tissue to the test site(11/11 subjects) and no fluid adsorption to the tissue (10/12 subjects).A summary of the drying time data for each of the drying time parametersis shown below:

Parameter Time, minutes [Mean (95% CI)] Visual appearance of dryness15.0 (9.6-20.4) No adhesion to the test site 10.0 (NA) No fluidadsorption to the tissue 10.4 (8.8-12.1) Time to 10% or Less of Peak14.2 (8.3-20.1) Weight Recovered

Considering the data for all the study parameters, it can be concludedthat the mean drying time for Topical Diclofenac Solution following asingle dose application was approximately 15 minutes, but there wasconsiderable variability among subjects with dryness occurring as earlyas 10 minutes in most subjects.

Beyond the 30 minute time point all visual appearance scores were 5 forall subjects, visual adsorption scores were 3, and differences betweenpostdose and predose tissue/vial weights were measured as 0.00 mg. Oncethe drug product has dried on the surface of the skin it is anticipatedthat residual unabsorbed diclofenac will be crystallized on the skinsurface will not be bioavailable. Therefore a patient being treated withTopical Diclofenac Solution can wash and shower after the product isdried without materially impacting the efficacy of the drug. The resultsof the study indicate that it is appropriate to instruct a user that apatient using Topical Diclofenac Solution should wait at least 30minutes after putting Topical Diclofenac Solution on the knee(s) beforetaking a shower or bath.

Example 10 Comparison of Elimination Constant after Single and MultipleDose Application of a Topical Solution Containing 1.5% Diclofenac Sodiumand 45.5% DMSO

It has been discovered that the elimination constant K_(el) (which isinversely related to the half life through K_(el)=ln(2)/T_(1/2)) for thetopical diclofenac solution of Examples 7 and 8 is highly statisticallysignificantly different depending on whether the solution is applied asa single dose or as multiple doses. In general it would be reasonable toassume that the effects of multiple doses of the topical solution wouldhave additive effects on the pharmacokinetics with the result that thehalf-life and K_(el) would be independent of dosage regime.Intriguingly, Examples 7 and 8 demonstrate that the apparent plasma halflife of diclofenac is increased after multiple doses of the solution areapplied as is evident in the log-linear plot showing average diclofenacplasma concentration after discontinuance of application of drugfollowing the protocols of the previous examples. The table belowprovides the half life and elimination constant for each subject in thestudies (NC indicates that half life was not determined due todifficulties in identifying an exponential tail in the experimentaldata).

Multi Dose Single Dose Subject # T_(1/2) (hr) K_(el) (hr⁻¹) Subject #T_(1/2) (hr) K_(el) (hr⁻¹) 1 68.8 0.010075 1 75.96 0.009125 2 66.850.010369 2 NC NC 3 NC NC 3 19.61 0.035347 4 43.41 0.015967 4 21.750.031869 5 NC NC 5 NC NC 6 128.94 0.005376 6 NC NC 7 NC NC 7 23.630.029333 9 72.74 0.009529 8 NC NC 10 90.29 0.007677 9 21.72 0.031913 11NC NC 10 66.44 0.010433 12 151.36 0.004579 11 NC NC 13 50.18 0.013813 1234.21 0.020262 14 46.64 0.014862 13 41.65 0.016642 15 86.11 0.00805  1428.13 0.024641 16 77.48 0.008946 15 30.29 0.022884 17 52.36 0.013238 1623.23 0.029838 18 43.36 0.015986 17 71.69 0.009669 19 157.25 0.004408 1819   0.036481 20 48.81 0.014201 Max 76.0  0.0365  Max 157.3 0.0160  Min19.0  0.0091  Min 43.4 0.0044  Mean 36.7  0.0237  Mean 79.0 0.0105  StdDev 20.8  0.0098  Std Dev 38.1 0.0040 

The distribution of the elimination constant K_(el) is well representedby a Normal distribution as shown in FIG. 9, which compares thecumulative distribution function of the K_(el) values from each studywith cumulative distribution functions for a Gaussian using mean andstandard deviation (Std Dev) values provided in the table above. At-test was performed and K_(el) was found to be highly significantlydifferent (p<0.001) depending on whether a single or multiple dosingregime of the topical solution was applied.

The reasons for the differences in diclofenac half life and K_(el) ondosing regime are at present unknown. In general drugs with longer halflives will tend to show more uniform plasma concentrations as a functionof time and may have improved safety profiles by reducing the maximumplasma concentration that a patient experiences and allowing efficacy tobe achieved with a lower overall dose. This point is particularlyimportant for patients that will use a relatively high risk drug such asdiclofenac on long-term basis to treat a chronic condition such asosteoarthritis. It will therefore be appreciated that the extension ofhalf-life observed with the multiple dosing regime of the topicaldiclofenac solution containing DMSO is an unexpected but fortuitousproperty of the solution.

Example 11 A Multi-Dose, Comparative, Exposure Study Under Maximum UseConditions Per Labeling of Both Pennsaid® Topical Solution (DiclofenacSodium Topical Solution 1.5% W/W and 45.5% w/w DMSO) and Solaraze® Gel(Diclofenac Sodium 3%)

A study was to conducted compare the exposure under maximum useconditions per labeling of diclofenac sodium following multipleapplications of PENNSAID® Topical Solution (diclofenac sodium topicalsolution) 1.5% w/w and Solaraze® Gel (diclofenac sodium 3%).

The study was a two-period, open-label, non-randomized, crossover study.All subjects applied PENNSAID® to both knees for 1 week during Period 1and Solaraze® to their actinic keratosis lesions for 4 weeks duringPeriod 2. A 3-week washout period was observed between the lastapplication of Period 1 and the first application of Period 2.

Thirty subjects were enrolled into the study. Thirty subjects completedPeriod 1 and 27 subjects completed Period 2. Pharmacokinetic andstatistical analyses were performed on data obtained from the 27subjects that completed the entire study.

The study population consisted of male and female subjects diagnosedwith actinic keratosis (AK) affecting at least 500 cm2 of skin on theface, head, scalp, neck, shoulders, arms, and/or upper trunk, notnecessarily continuous, of which at least 100 cm2 of the total affectedarea was on the face, head or scalp. Subjects were required to have atotal of at least 20 non-hypertrophic AK lesions on all areas combinedand a total of at least 6 non-hypertrophic AK lesions on the face, heador scalp.

During Period 1 subjects applied 40 drops (approx. 1.2 mL) q.i.d. ofPENNSAID® Topical Solution (diclofenac sodium topical solution) 1.5% w/w(Nuvo Research Inc.) to each knee, 80 drops total per application, onDays 1 to 7 and dosed once on the morning of Day 8.

During Period 2 subjects applied 0.02 g/cm2 b.i.d of Solaraze® Gel(diclofenac sodium 3%) to the area of skin affected by actinickeratosis, up to a maximum of 1000 cm2 area on Days 1 to 27 and once onthe morning of Day 28.

Using a validated HPLC method, plasma diclofenac sodium was analyzedfrom blood samples collected at the following timepoints (relative tofirst dose of the day):

Period 1 (PENNSAID®):

Day 1: 0.0 hour (pre-dose)Day 6 and 7: 0.0 hour (pre-dose)Day 8: 0.0 hour (pre-dose), 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0and 6.0 hour

Period 2 (Solaraze®):

Day 1: 0.0 hour (pre-dose)Day 26 and 27: 0.0 hour (pre-dose)Day 28: 0.0 hour (pre-dose), 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0,6.0, 8.0, 10.0 and 12.0 hour

Pharmacokinetic parameters for plasma diclofenac sodium were calculatedfor each treatment period by standard noncompartmentalmethods:C_(max(ss)), C_(mm(ss)), C_(avg(ss)), AUC_(T(ss)),AUC_(0-24(ss)), T_(max(ss)). For PENNSAID®, AUC_(T(ss)) was calculatedover the dosing interval of 0-6 hours, and for Solaraze®, AUC_(T(ss))was calculated over the dosing interval of 0-12 hours. For eachtreatment AUC_(T(ss)) was adjusted to a 24-hour exposure parameter,AUC_(0-24(ss)) (calculated as AUC_(T(ss))×2 for Solaraze® andAUC_(T(ss))×4 for PENNSAID®), so that a comparison between the exposureof each treatment was assessed on a daily basis.

Steady-state of plasma diclofenac was attained within 8 days forPENNSAID® and within 28 days for Solaraze®. The calculated C_(max(ss)),C_(mm(ss)), C_(avg(ss)), AUC_(T(ss)) and AUC_(0-24(ss)) of diclofenacwere substantially lower and T_(max(ss)) was shorter following themaximum therapeutic dose of PENNSAID® compared to that observedfollowing the application of Solaraze® as per label as summarized in thetable below.

Summary Statistics of Pharmacokinetic Parameters* (mean [SD]) PENNSAID ®Solaraze ® PK Parameter N = 30 N = 27 C_(max(ss)) (ng/mL) 35.0 (28.6)125.9 (119.3) C_(min(ss)) (ng/mL) 16.7 (10.4) 30.4 (19.4) C_(avg(ss))(ng/mL) 24.2 (16.3) 72.3 (63.5) AUC_(T(ss)) (ng · h/mL) 144.9 (98.0)868.1 (762.2) AUC_(0-24(ss)) (ng · h/mL) 579.7 (392.2) 1736.3 (1524.4)T_(max(ss))** (h) 1.0 2.5 *uncorrected for surface area, **median forT_(max(ss))

The analysis of the PENNSAID®/Solaraze® ratio (and corresponding 90%confidence interval [CI]) of the geometric mean for ln-transformedC_(max(ss)) and AUC_(0-24 (ss)) for both uncorrected and corrected forsurface area data (i.e. making comparison C_(max(ss)) and AUC_(0-24(ss))per unit area of skin treated) revealed the rate and extent ofbioavailabilty of diclofenac following the maximum therapeutic dose ofPENNSAID® were approximately ⅓ that of Solaraze®, with upper confidencelimits well below the 80-125% range.

Mean Relative Bioavailability Pharmacokinetic Parameters* (lntransformed, N = 27) Parameter PENNSAID ® Solaraze ® Ratio, % (90% CI)Uncorrected C_(max(ss)) 26.9 91.8 29.4 (21.7-39.7) AUC_(0-24(ss)) 474.21346.2 35.2 (27.6-45.0) Corrected for Surface Area C_(max(ss)) 0.0250.0739 34.2 (25.0-46.9) AUC_(0-24(ss)) 0.39 1.24 31.5 (24.4-40.7) *leastsquare mean

Attachment Full Prescribing Information Warning: Cardiovascular andGastrointestinal Risk Cardiovascular Risk

-   -   Nonsteroidal anti-inflammatory drugs (NSAIDs) may cause an        increased risk of serious cardiovascular thrombotic events,        myocardial infarction, and stroke, which can be fatal. This risk        may increase with duration of use. Patients with cardiovascular        disease or risk factors for cardiovascular disease may be at        greater risk [see Warnings and Precautions (5.1)].    -   PENNSAID Topical Solution is contraindicated in the        peri-operative setting of coronary artery bypass graft (CABG)        surgery [see Contraindications (4)].

Gastrointestinal Risk

-   -   NSAIDs cause an increased risk of serious gastrointestinal        adverse events including bleeding, ulceration, and perforation        of the stomach or intestines, which can be fatal. These events        can occur at any time during use and without warning symptoms.        Elderly patients are at greater risk for serious        gastrointestinal events [see Warnings and Precautions (5.2)].

1. INDICATIONS AND USAGE

PENNSAID Topical Solution is a nonsteroidal anti-inflammatory drug(NSAID) indicated for the treatment of signs and symptoms ofosteoarthritis of the knee(s).

2. DOSAGE AND ADMINISTRATION

2.1 General Instructions

For the relief of the signs and symptoms of osteoarthritis of theknee(s), the recommended dose is 40 drops per knee, 4 times a day.

Apply PENNSAID Topical Solution to clean, dry skin.

To avoid spillage, dispense PENNSAID 10 drops at a time either directlyonto the knee or first into the hand and then onto the knee. SpreadPENNSAID Topical Solution evenly around front, back and sides of theknee. Repeat this procedure until 40 drops have been applied and theknee is completely covered with solution.

To treat the other knee, if symptomatic, repeat the procedure.

Application of PENNSAID Topical Solution in an amount exceeding or lessthan the recommended dose has not been studied and is therefore notrecommended.

2.2 Special Precautions

-   -   Avoid showering/bathing for at least 30 minutes after the        application of PENNSAID Topical Solution to the treated knee.    -   Wash and dry hands after use.    -   Do not apply PENNSAID Topical Solution to open wounds.    -   Avoid contact of PENNSAID Topical Solution with eyes and mucous        membranes.    -   Do not apply external heat and/or occlusive dressings to treated        knees.    -   Avoid wearing clothing over the PENNSAID Topical        Solution-treated knee until the treated knee is dry.    -   Protect the treated knee(s) from sunlight.    -   Wait until the treated area is dry before applying sunscreen,        insect repellant, lotion, moisturizer, cosmetics, or other        topical medication to the same knee you have just treated with        PENNSAID Topical Solution.

3. DOSAGE FORMS AND STRENGTHS

1.5% w/w topical solution

4. CONTRAINDICATIONS

PENNSAID Topical Solution is contraindicated in patients with a knownhypersensitivity to diclofenac sodium or any other component of PENNSAIDTopical Solution.

PENNSAID Topical Solution is contraindicated in patients who haveexperienced asthma, urticaria, or allergic-type reactions after takingaspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-likereactions to NSAIDs have been reported in such patients [see Warningsand Precautions (5.7, 5.10)].

PENNSAID Topical Solution is contraindicated in the setting of coronaryartery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)].

5. WARNINGS AND PRECAUTIONS

5.1 Cardiovascular Thrombotic Events

Clinical trials of several oral COX-2 selective and nonselective NSAIDsof up to three years duration have shown an increased risk of seriouscardiovascular (CV) thrombotic events, myocardial infarction (MI), andstroke, which can be fatal. All NSAIDs, including PENNSAID and COX-2selective and nonselective orally administered NSAIDS, may have asimilar risk. Patients with known CV disease or risk factors for CVdisease may be at greater risk. To minimize the potential risk for anadverse CV event in patients treated with an NSAID, use the lowesteffective dose for the shortest duration possible. Physicians andpatients should remain alert for the development of such events, even inthe absence of previous CV symptoms. Inform patients about the signsand/or symptoms of serious CV events and the steps to take if theyoccur.

Two large, controlled, clinical trials of an orally administered COX-2selective NSAID for the treatment of pain in the first 10-14 daysfollowing CABG surgery found an increased incidence of myocardialinfarction and stroke [see Contraindications (4)].

There is no consistent evidence that concurrent use of aspirin mitigatesthe increased risk of serious CV thrombotic events associated with NSAIDuse. The concurrent use of aspirin and NSAIDs, such as diclofenac, doesincrease the risk of serious GI events [see Warnings and Precautions(5.2)].

5.2 Gastrointestinal Effects—Risk of GI Ulceration, Bleeding, andPerforation

NSAIDs, including diclofenac, can cause serious gastrointestinal (GI)adverse events including bleeding, ulceration, and perforation of thestomach, small intestine, or large intestine, which can be fatal. Theseserious adverse events can occur at any time, with or without warningsymptoms, in patients treated with NSAIDs. Only one in five patients whodevelop a serious upper GI adverse event on NSAID therapy issymptomatic. Upper GI ulcers, gross bleeding, or perforation caused byNSAIDs occur in approximately 1% of patients treated for 3-6 months, andin about 2-4% of patients treated for one year. These trends continuewith longer duration of use, increasing the likelihood of developing aserious GI event at some time during the course of therapy. However,even short-term therapy is not without risk.

Prescribe NSAIDs, including Pennsaid, with extreme caution in those witha prior history of ulcer disease or gastrointestinal bleeding. Patientswith a prior history of peptic ulcer disease and/or gastrointestinalbleeding who use NSAIDs have a greater than 10-fold increased risk fordeveloping a GI bleed compared to patients with neither of these riskfactors. Other factors that increase the risk of GI bleeding in patientstreated with NSAIDs include concomitant use of oral corticosteroids oranticoagulants, longer duration of NSAID therapy, smoking, use ofalcohol, older age, and poor general health status. Most spontaneousreports of fatal GI events are in elderly or debilitated patients andtherefore, use special care when treating this population.

To minimize the potential risk for an adverse GI event, use the lowesteffective dose for the shortest possible duration. Remain alert forsigns and symptoms of GI ulceration and bleeding during diclofenactherapy and promptly initiate additional evaluation and treatment if aserious GI adverse event is suspected. For high-risk patients, consideralternate therapies that do not involve NSAIDs.

5.3 Hepatic Effects

Borderline elevations (less than 3 times the upper limit of the normal[ULN] range) or greater elevations of transaminases occurred in about15% of oral diclofenac-treated patients in clinical trials ofindications other than acute pain. Of the markers of hepatic function,ALT (SGPT) is recommended for the monitoring of liver injury.

In clinical trials of a oral diclofenac—misoprostol combination product,meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT)occurred in about 2% of approximately 5,700 patients at some time duringdiclofenac treatment (ALT was not measured in all studies).

In an open-label, controlled trial of 3,700 patients treated for 2-6months, patients with oral diclofenac were monitored first at 8 weeksand 1,200 patients were monitored again at 24 weeks. Meaningfulelevations of ALT and/or AST occurred in about 4% of the 3,700 patientsand included marked elevations (>8 times the ULN) in about 1% of the3,700 patients. In this open-label study, a higher incidence ofborderline (less than 3 times the ULN), moderate (3-8 times the ULN),and marked (>8 times the ULN) elevations of ALT or AST was observed inpatients receiving diclofenac when compared to other NSAIDs. Elevationsin transaminases were seen more frequently in patients withosteoarthritis than in those with rheumatoid arthritis. Almost allmeaningful elevations in transaminases were detected before patientsbecame symptomatic.

Abnormal tests occurred during the first 2 months of therapy with oraldiclofenac in 42 of the 51 patients in all trials who developed markedtransaminase elevations. In postmarketing reports, cases of drug-inducedhepatotoxicity have been reported in the first month, and in some cases,the first 2 months of NSAID therapy.

Postmarketing surveillance has reported cases of severe hepaticreactions, including liver necrosis, jaundice, fulminant hepatitis withand without jaundice, and liver failure. Some of these reported casesresulted in fatalities or liver transplantation.

In a European retrospective population-based, case-controlled study, 10cases of oral diclofenac associated drug-induced liver injury withcurrent use compared with non-use of diclofenac were associated with astatistically significant 4-fold adjusted odds ratio of liver injury. Inthis particular study, based on an overall number of 10 cases of liverinjury associated with diclofenac, the adjusted odds ratio increasedfurther with female gender, doses of 150 mg or more, and duration of usefor more than 90 days.

Measure transaminases (ALT and AST) periodically in patients receivinglong-term therapy with diclofenac, because severe hepatotoxicity maydevelop without a prodrome of distinguishing symptoms. The optimum timesfor making the first and subsequent transaminase measurements are notknown. Based on clinical trial data and postmarketing experiences,monitor transaminases within 4 to 8 weeks after initiating treatmentwith diclofenac. However, severe hepatic reactions can occur at any timeduring treatment with diclofenac. If abnormal liver tests persist orworsen, if clinical signs and/or symptoms consistent with liver diseasedevelop, or if systemic manifestations occur (e.g., eosinophilia, rash,abdominal pain, diarrhea, dark urine, etc.), discontinue PENNSAIDimmediately.

To minimize the possibility that hepatic injury will become severebetween transaminase measurements, inform patients of the warning signsand symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy,diarrhea, pruritus, jaundice, right upper quadrant tenderness, and“flulike” symptoms), and the appropriate action to take if these signsand symptoms appear.

To minimize the potential risk for an adverse liver-related event inpatients treated with PENNSAID, use the lowest effective dose for theshortest duration possible. Exercise caution when prescribing PENNSAIDwith concomitant drugs that are known to be potentially hepatotoxic(e.g. acetaminophen, certain antibiotics, antiepileptics). Cautionpatients to avoid taking unprescribed acetaminophen while usingPennsaid.

5.4 Hypertension

NSAIDs, including diclofenac, can lead to new onset or worsening ofpreexisting hypertension, either of which may contribute to theincreased incidence of CV events. Use NSAIDs, including Pennsaid, withcaution in patients with hypertension. Monitor blood pressure (BP)closely during the initiation of NSAID treatment and throughout thecourse of therapy.

Patients taking ACE inhibitors, thiazides or loop diuretics may haveimpaired response to these therapies when taking NSAIDs.

5.5 Congestive Heart Failure and Edema

Fluid retention and edema have been observed in some patients treatedwith NSAIDs, including PENNSAID Topical Solution. Use PENNSAID TopicalSolution with caution in patients with fluid retention or heart failure.

5.6 Renal Effects

Use caution when initiating treatment with Pennsaid in patients withconsiderable dehydration.

Long-term administration of NSAIDs has resulted in renal papillarynecrosis and other renal injury. Renal toxicity has also been seen inpatients in whom renal prostaglandins have a compensatory role in themaintenance of renal perfusion. In these patients, administration of anNSAID may cause a dose-dependent reduction in prostaglandin formationand, secondarily, in renal blood flow, which may precipitate overt renaldecompensation. Patients at greatest risk of this reaction are thosewith impaired renal function, heart failure, liver dysfunction, thosetaking diuretics and ACE inhibitors, and the elderly. Discontinuation ofNSAID therapy is usually followed by recovery to the pretreatment state.

No information is available from controlled clinical studies regardingthe use of PENNSAID Topical Solution in patients with advanced renaldisease. Therefore, treatment with PENNSAID Topical Solution is notrecommended in patients with advanced renal disease. If PENNSAID TopicalSolution therapy is initiated, close monitoring of the patient's renalfunction is advisable.

5.7 Anaphylactoid Reactions

As with other NSAIDs, anaphylactoid reactions may occur in patientswithout prior exposure to PENNSAID Topical Solution. Do not prescribePENNSAID Topical Solution to patients with the aspirin triad. Thissymptom complex typically occurs in asthmatic patients who experiencerhinitis with or without nasal polyps, or who exhibit severe,potentially fatal bronchospasm after taking aspirin or other NSAIDs [seeContraindications (4) and Warnings and Precautions (5.10)]. Seekemergency help in cases where an anaphylactoid reaction occurs.

5.8 Skin Reactions

Do not apply PENNSAID Topical Solution to open skin wounds, infections,inflammations, or exfoliative dermatitis, as it may affect absorptionand tolerability of the drug.

NSAIDs, including PENNSAID Topical Solution, can cause serious skinadverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome(SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Theseserious events may occur without warning. Inform patients about thesigns and symptoms of serious skin manifestations, and discontinue useof the drug at the first appearance of skin rash or any other signs ofhypersensitivity.

5.9 Pregnancy

PENNSAID Topical Solution should not be used by pregnant or nursingwomen or those intending to become pregnant.

5.10 Preexisting Asthma

Patients with asthma may have aspirin-sensitive asthma. The use ofaspirin in patients with aspirin-sensitive asthma has been associatedwith severe bronchospasm, which can be fatal. Since cross-reactivity,including bronchospasm, between aspirin and other nonsteroidalanti-inflammatory drugs has been reported in such aspirin-sensitivepatients, do not administer PENNSAID Topical Solution to patients withthis form of aspirin sensitivity and use with caution in patients withpreexisting asthma.

5.11 Sun Exposure

Instruct patients to avoid exposure to natural or artificial sunlight ontreated knee(s) because studies in animals indicated topical diclofenactreatment resulted in an earlier onset of ultraviolet light-induced skintumors. The potential effects of PENNSAID Topical Solution on skinresponse to ultraviolet damage in humans are not known.

5.12 Eye Exposure

Avoid contact of PENNSAID Topical Solution with eyes and mucosa. Advisepatients that if eye contact occurs, immediately wash out the eye withwater or saline and consult a physician if irritation persists for morethan an hour.

5.13 Oral Nonsteroidal Anti-Inflammatory Drugs

Concomitant use of oral NSAIDs with PENNSAID Topical Solution resultedin a higher rate of rectal hemorrhage, more frequent abnormalcreatinine, urea and hemoglobin. Therefore, do not use combinationtherapy with PENNSAID Topical Solution and an oral NSAID unless thebenefit outweighs the risk and conduct periodic laboratory evaluations.

5.14 Corticosteroid Treatment

PENNSAID Topical Solution cannot be expected to substitute forcorticosteroids or to treat corticosteroid insufficiency. Abruptdiscontinuation of corticosteroids may lead to exacerbation ofcorticosteroid-response illness. For patients on prolongedcorticosteroid therapy, taper slowly if a decision is made todiscontinue corticosteroids.

5.15 Inflammation

The pharmacological activity of PENNSAID Topical Solution in reducinginflammation, and possibly fever, may diminish the utility of thesediagnostic signs in detecting complications of presumed noninfectious,painful conditions.

5.16 Hematological Effects

The effects of PENNSAID Topical Solution on platelet function werestudied in 10 healthy subjects administered 80 drops four times a dayfor 7 days. There was no significant change in platelet aggregationfollowing one week of treatment [see Clinical Pharmacology (12.4)].

Anemia is sometimes seen in patients receiving NSAIDs. This may be dueto fluid retention, occult or gross GI blood loss, or an incompletelydescribed effect upon erythropoiesis. Check hemoglobin or hematocrit ofpatients on PENNSAID Topical Solution if they exhibit any signs orsymptoms of anemia or blood loss.

NSAIDs inhibit platelet aggregation and have been shown to prolongbleeding time in some patients. Unlike aspirin, their effect on plateletfunction is quantitatively less, of shorter duration and reversible.Carefully monitor patients receiving PENNSAID Topical Solution who maybe adversely affected by alterations in platelet function, such as thosewith coagulation disorders or patients receiving anticoagulants.

5.17 Monitoring

Because serious GI tract ulcerations and bleeding can occur withoutwarning symptoms in patients taking NSAIDs, monitor patients for signsor symptoms of GI bleeding. Check CBC and a chemistry profileperiodically in patients on long-term treatment with NSAIDs. DiscontinuePENNSAID Topical Solution if abnormal liver tests or renal tests persistor worsen.

6. ADVERSE REACTIONS

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions,adverse reaction rates observed in the clinical trials of a drug cannotbe directly compared to rates in the clinical trials of another drug andmay not reflect the rates observed in practice.

The data described below reflect exposure to PENNSAID Topical Solutionof 911 patients treated between 4 and 12 weeks (mean duration of 49days) in seven Phase 3 controlled trials, as well as exposure of 793patients treated in an open-label study, including 463 patients treatedfor at least 6 months, and 144 patients treated for at least 12 months.The population mean age was approximately 60 years, 89% of patients wereCaucasians, 64% were females, and all patients had primaryosteoarthritis. The most common adverse events with PENNSAID TopicalSolution were application site skin reactions. These events were themost common reason for withdrawing from the studies.

Application Site Reactions:

In controlled trials, the most common treatment-related adverse eventsin patients receiving PENNSAID Topical Solution were application siteskin reactions. Application site reactions were characterized by one ormore of the following: dryness, erythema, induration, vesicles,paresthesia, pruritus, vasodilation, acne, and urticaria. The mostfrequent of these reactions were dry skin (32%), contact dermatitischaracterized by skin erythema and induration (9%), contact dermatitiswith vesicles (2%) and pruritus (4%). In one controlled trial, a higherrate of contact dermatitis with vesicles (4%) was observed aftertreatment of 152 subjects with the combination of PENNSAID TopicalSolution and oral diclofenac. In the open label uncontrolled long-termsafety study, contact dermatitis occurred in 13% and contact dermatitiswith vesicles in 10% of patients, generally within the first 6 months ofexposure, leading to a withdrawal rate for an application site event of14%.

Adverse Events Common to the NSAID Class:

In controlled trials, subjects treated with PENNSAID Topical Solutionexperienced some adverse events associated with the NSAID class morefrequently than subjects using placebo (constipation, diarrhea,dyspepsia, nausea, flatulence, abdominal pain, edema; see Table 1). Thecombination of PENNSAID Topical Solution and oral diclofenac, comparedto oral diclofenac alone, resulted in a higher rate of rectal hemorrhage(3% vs. less than 1%), and more frequent abnormal creatinine (12% vs.7%), urea (20% vs. 12%), and hemoglobin (13% vs. 9%), but no differencein elevation of liver transaminases.

Table 1 lists all adverse reactions occurring in 1% of patientsreceiving PENNSAID Topical Solution, where the rate in the PENNSAIDTopical Solution group exceeded placebo, from seven controlled studiesconducted in patients with osteoarthritis. Since these trials were ofdifferent durations, these percentages do not capture cumulative ratesof occurrence.

TABLE 1 Adverse Reactions occurring in ≧1% of patients treated withPENNSAID ® Topical Solution in placebo and oral diclofenac-controlledtrials. Treatment Group: PENNSAID ® Topical Solution Topical Placebo N =911 N = 332 Adverse Reaction^(†) N (%) N (%) Dry Skin (Application Site)292 (32) 17 (5) Contact Dermatitis (Application 83 (9) 6 (2) Site)Dyspepsia 72 (8) 13 (4) Abdominal Pain 54 (6) 10 (3) Flatulence 35 (4) 1(<1) Pruritus (Application Site) 34 (4) 7 (2) Diarrhea 33 (4) 7 (2)Nausea 33 (4) 3 (1) Pharyngitis 40 (4) 13 (4) Constipation 29 (3) 1 (<1)Edema 26 (3) 0 Rash (Non-Application Site) 25 (3) 5 (2) Infection 25 (3)8 (2) Ecchymosis 19 (2) 1 (<1) Dry Skin (Non-Application Site) 19 (2) 1(<1) Contact Dermatitis, vesicles 18 (2) 0 (Application Site)Paresthesia (Non-Application 14 (2) 3 (<1) Site) Accidental Injury 22(2) 7 (2) Pruritus (Non-Application Site) 15 (2) 2 (<1) Sinusitis 10 (1)2 (<1) Halitosis 11 (1) 1 (<1) Application Site Reaction (not 11 (1) 3(<1) otherwise specified) ^(†)Preferred Term according to COSTART

6.2 Postmarketing Experience

In non-US post-marketing surveillance, the following adverse reactionshave been reported during post-approval use of PENNSAID TopicalSolution. Because these reactions are reported voluntarily from apopulation of uncertain size, it is not always possible to reliablyestimate their frequency or establish a causal relationship to drugexposure.

-   -   Body as a whole: abdominal pain, accidental injury, allergic        reaction, asthenia, back pain, body odor, chest pain, edema,        face edema, halitosis, headache, lack of drug effect, neck        rigidity, pain    -   Cardiovascular: palpitation, cardiovascular disorder    -   Digestive: diarrhea, dry mouth, dyspepsia, gastroenteritis,        decreased appetite, mouth ulceration, nausea, rectal hemorrhage,        ulcerative stomatitis    -   Metabolic and Nutritional: creatinine increased    -   Musculoskeletal: leg cramps, myalgia    -   Nervous: depression, dizziness, drowsiness, lethargy,        paresthesia, paresthesia at application site    -   Respiratory: asthma, dyspnea, laryngismus, laryngitis,        pharyngitis    -   Skin and Appendages: At the Application Site: contact        dermatitis, contact dermatitis with vesicles, dry skin,        pruritus, rash; Other Skin and Appendages Adverse Reactions:        eczema, rash, pruritus, skin discoloration, urticaria    -   Special senses: abnormal vision, blurred vision, cataract, ear        pain, eye disorder, eye pain, taste perversion

7. DRUG INTERACTIONS

Drug interactions with the use of PENNSAID Topical Solution have notbeen studied. The following drug interactions [sections 7.1 to 7.7] arenoted for oral diclofenac sodium.

7.1 Aspirin

When diclofenac is administered with aspirin, the binding of diclofenacto protein is reduced, although the clearance of free diclofenac is notaltered. The clinical significance of this interaction is not known;however, as with other NSAIDs, concomitant administration of diclofenacand aspirin is not generally recommended because of the potential ofincreased adverse effects.

7.2 Anticoagulants

The effects of anticoagulants such as warfarin and NSAIDs on GI bleedingare synergistic, such that users of both drugs together have a risk ofserious GI bleeding higher than users of either drug alone.

7.3 ACE-Inhibitors

NSAIDs may diminish the antihypertensive effect of angiotensinconverting enzyme (ACE) inhibitors. Consider this interaction inpatients taking NSAIDs concomitantly with ACE-inhibitors.

7.4 Diuretics

Clinical studies, as well as post-marketing observations, have shownthat NSAIDs can reduce the natriuretic effect of furosemide andthiazides in some patients. The response has been attributed toinhibition of renal prostaglandin synthesis. During concomitant therapywith NSAIDs, observe the patient closely for signs of renal failure [seeWarnings and Precautions (5.6)], as well as to assure diuretic efficacy.

7.5 Lithium

NSAIDs have produced an elevation of plasma lithium levels and areduction in renal lithium clearance. The mean minimum lithiumconcentration increased 15% and the renal clearance was decreased byapproximately 20%. These effects have been attributed to inhibition ofrenal prostaglandin synthesis by the NSAID. Thus, when NSAIDs, includingdiclofenac, and lithium are administered concurrently, observe patientscarefully for signs of lithium toxicity.

7.6 Methotrexate

NSAIDs have been reported to competitively inhibit methotrexateaccumulation in rabbit kidney slices. This may indicate that they couldenhance the toxicity of methotrexate. Use caution when NSAIDs, includingdiclofenac, are administered concomitantly with methotrexate.

7.7 Cyclosporine

Diclofenac, like other NSAIDs, may affect renal prostaglandins andincrease the toxicity of certain drugs. Therefore, concomitant therapywith diclofenac may increase cyclosporine's nephrotoxicity. Use cautionwhen diclofenac is administered concomitantly with cyclosporine.

7.8 Oral Nonsteroidal Anti-Inflammatory Drugs

Concomitant use of oral NSAIDs with PENNSAID Topical Solution has beenevaluated in one Phase 3 controlled trial and in combination with oraldiclofenac, compared to oral diclofenac alone, resulted in a higher rateof rectal hemorrhage (3% vs. less than 1%), and more frequent abnormalcreatinine (12% vs. 7%), urea (20% vs. 12%) and hemoglobin (13% vs. 9%).Therefore, do not use combination therapy with PENNSAID Topical Solutionand an oral NSAID unless the benefit outweighs the risk and conductperiodic laboratory evaluations.

7.9 Topical Treatments

Instruct patients that before applying sunscreen, insect repellant,lotion, moisturizer, cosmetics, or other topical medication to the sameskin surface of the knee treated with PENNSAID Topical Solution, theymust wait until the treated area is completely dry.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C prior to 30 weeks gestation; Category D starting 30weeks gestation.

Teratogenic Effects:

There are no adequate and well-controlled studies of PENNSAID TopicalSolution in pregnant women. PENNSAID Topical Solution should not be usedby pregnant women as its safe use has not been adequately determined andstarting at 30 weeks gestation, diclofenac and other NSAIDs should beavoided by pregnant women as premature closure of the ductus arteriosusin the fetus may occur. Developmental studies in animals demonstratedthat diclofenac sodium administration did not produce teratogenicitydespite the induction of maternal toxicity and fetal toxicity in mice atdoses up to 20 mg/kg/day (0.6-fold the maximum recommended human dose[MRHD] of 154 mg/day based on body surface area comparison), and in ratsand rabbits at doses up to 10 mg/kg/day (approximately 0.6-fold and1.3-fold the MRHD, respectively). Published reproductive anddevelopmental studies of dimethyl sulfoxide (DMSO, the solvent used inPENNSAID Topical Solution) are equivocal as to potential teratogenicity.

Nonteratogenic Effects

In rats, maternally toxic doses of diclofenac were associated withdystocia, prolonged gestation, reduced fetal weights and growth, andreduced fetal survival.

8.2 Labor and Delivery

The effects of PENNSAID Topical Solution on labor and delivery inpregnant women are unknown. In rat studies maternal exposure todiclofenac, as with other NSAID drugs, known to inhibit prostaglandinsynthesis, increased the incidence of dystocia, delayed parturition, anddecreased offspring survival.

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk; however,there is a case report in the literature indicating that diclofenac canbe detected at low levels in breast milk. Because many drugs areexcreted in human milk and because of the potential for serious adversereactions in nursing infants from PENNSAID Topical Solution, a decisionshould be made whether to discontinue nursing or to discontinue thedrug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not beenestablished.

8.5 Geriatric Use

Of the 911 patients treated with PENNSAID Topical Solution in sevencontrolled, Phase 3 clinical trials, 444 subjects were 65 years of ageand over. There was no age-related difference in the incidence ofadverse events. Of the 793 patients treated with PENNSAID TopicalSolution in one open-labeled safety trial, 334 subjects were 65 years ofage and over including 107 subjects 75 and over. There was no differencein the incidence of adverse events with long-term exposure to PENNSAIDTopical Solution for this elderly population. As with any NSAID, usecaution in treating the elderly (65 years and older) and it may beuseful to monitor renal function since they are more likely to havedecreased baseline renal function.

10. OVERDOSAGE

There have been no known experiences of overdose with PENNSAID TopicalSolution.

Symptoms following acute NSAID overdose are usually limited to lethargy,drowsiness, nausea, vomiting, and epigastric pain, which are generallyreversible with supportive care. Gastrointestinal bleeding can occur.Hypertension, acute renal failure, respiratory depression and coma mayoccur, but are rare. Anaphylactoid reactions have been reported withtherapeutic ingestion of NSAIDs, and may occur following an overdose.

Manage patients using symptomatic and supportive care following an NSAIDoverdose. There are no specific antidotes. Emesis is not recommended dueto a possibility of aspiration and subsequent respiratory irritation byDMSO contained in PENNSAID Topical Solution. Activated charcoal (60 to100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic maybe indicated in patients seen within 4 hours of ingestion with symptomsor following a large overdose (5 to 10 times the usual dose). Forceddiuresis, alkalinization of urine, hemodialysis, or hemoperfusion maynot be useful due to high protein binding.

For additional information about overdose treatment, call a poisoncontrol center (1-800-222-1222).

11. DESCRIPTION

PENNSAID Topical Solution is a clear, colorless to faintly pink-orangesolution for topical application.

PENNSAID Topical Solution contains 1.5% w/w diclofenac sodium, abenzene-acetic acid derivative that is a nonsteroidal anti-inflammatorydrug (NSAID), designated chemically as 2-[(2,6-dichlorophenyl) amino]benzeneacetic acid, monosodium salt. The molecular weight is 318.14. Itsmolecular formula is

C₁₄H₁₀Cl₂NNaO₂ and it has the following structural formula:

Each 1 mL of solution contains 16.05 mg of diclofenac sodium. Inaddition, PENNSAID Topical Solution contains the following inactiveingredients: dimethyl sulfoxide USP (DMSO, 45.5% w/w), propylene glycol,alcohol, glycerin and purified water.

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of diclofenac is similar to that of othernonsteroidal anti-inflammatory drugs. Diclofenac inhibits the enzyme,cyclooxygenase (COX), an early component of the arachidonic acidcascade, resulting in the reduced formation of prostaglandins,thromboxanes and prostacylin. It is not completely understood howreduced synthesis of these compounds results in therapeutic efficacy.

12.2 Pharmacodynamics

Diclofenac, the active component of PENNSAID Topical Solution hasanti-inflammatory, anti-nociception, and antipyretic effects.

12.3 Pharmacokinetics

After topical administration to healthy human volunteers of single andmultiple maximum doses of PENNSAID Topical Solution, 40 drops(approximately 1.2 mL) to each knee (80 drops total dose), the followingdiclofenac pharmacokinetic parameters were obtained: (see Table 2).

TABLE 2 Single-dose (80 drops) and Multiple Dose (80 drops four timesdaily for 7 days) PENNSAID Topical Solution Pharmacokinetic ParametersDiclofenac sodium Normal Adults [N = 19] Normal Adults [N = 18] (Age:18-55 years) Pharmacokinetic (Age: 18-55 years) Multiple Dose ParametersSingle Dose Four times daily for 7 days AUC_(0-t) 177.5 ± 72.6 ng · h/mL695.4 ± 348.9 ng · h/mL AUC_(0-inf) 196.3 ± 68.5 ng · h/mL 745.2 ± 374.7ng · h/mL Plasma C_(max)  8.1 ± 5.9 ng/mL  19.4 ± 9.3 ng/mL PlasmaT_(max) (h) 11.0 ± 6.4  4.0 ± 6.5 Plasma t_(1/2) (h) 36.7 ± 20.8 79.0 ±38.1 K_(el) (h⁻¹) 0.024 ± 0.010 0.011 ± 0.004 CL/F (L/h) 244.7 ± 84.7¹ — ¹Apparent total body clearance

Absorption

Diclofenac systemic exposure from PENNSAID application (4 times dailyfor 1 week) was approximately ⅓ of the diclofenac systemic exposure fromthe Solaraze (diclofenac topical gel) application (twice daily for 4weeks).

Distribution

Diclofenac is more than 99% bound to human serum proteins, primarily toalbumin.

Diclofenac diffuses into and out of the synovial fluid. Diffusion intothe joint occurs when plasma levels are higher than those in thesynovial fluid, after which the process reverses and synovial fluidlevels are higher than plasma levels. It is not known whether diffusioninto the joint plays a role in the effectiveness of diclofenac.

Metabolism

Five diclofenac metabolites have been identified in human plasma andurine. The metabolites include 4′-hydroxy-, 5-hydroxy-, 3′-hydroxy-,4′,5-dihydroxy- and 3′-hydroxy-4′-methoxy diclofenac. The majordiclofenac metabolite, 4′-hydroxy-diclofenac, has very weakpharmacologic activity. The formation of 4′-hydroxy diclofenac isprimarily mediated by CPY2C9. Both diclofenac and its oxidativemetabolites undergo glucuronidation or sulfation followed by biliaryexcretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediatedby CPY2C8 may also play a role in diclofenac metabolism. CYP3A4 isresponsible for the formation of minor metabolites, 5-hydroxy and3′-hydroxy-diclofenac.

Excretion

Diclofenac is eliminated through metabolism and subsequent urinary andbiliary excretion of the glucuronide and the sulfate conjugates of themetabolites.

Little or no free unchanged diclofenac is excreted in the urine.

Special Populations

-   -   Pediatric: The pharmacokinetics of PENNSAID has not been        investigated in pediatric patients.    -   Race: Pharmacokinetic differences due to race have not been        studied.

12.4 Platelets

The effect of PENNSAID Topical Solution on platelet function wasevaluated in 10 healthy human volunteers as a sub-study of amultiple-dose pharmacokinetic study [see Pharmacokinetics (12.3)].Average (range) platelet aggregation time following stimulation withadenosine diphosphate, collagen, epinephrine and arachidonic acid was101.3% (73.3-128.1), 99.8% (69.6-112.9), 109.9% (66.2-178.1) and 99.0%(15.5-126.6) of baseline value, respectively. These results indicatethat there was no effect on platelet aggregation after application ofthe maximum clinical dose for 7 days [see Pharmacokinetics (12.3)].

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility.

Carcinogenicity studies in mice and rats administered diclofenac sodiumas a dietary constituent for 2 years resulted in no significantincreases in tumor incidence at does up to 2 mg/kg/day corresponding toapproximately 0.35- and 0.7-fold (mouse and rat, respectively) of themaximum recommended human topical dose (MRHD) of PENNSAID TopicalSolution (based on apparent bioavailability and body surface areacomparison).

In a dermal carcinogenicity study conducted in albino mice, dailytopical applications of diclofenac sodium for two years atconcentrations up to −0.035% diclofenac sodium (a 43-fold lowerdiclofenac sodium concentration than present in PENNSAID TopicalSolution) did not increase neoplasm incidence.

In a photococarcinogenicity study conducted in hairless mice, topicalapplication of diclofenac sodium at doses up to 0.035% diclofenac sodium(a 43-fold lower diclofenac sodium concentration than present inPENNSAID Topical Solution) resulted in an earlier median time of onsetof tumors.

-   -   Mutagenesis: Diclofenac was not mutagenic or clastogenic in a        battery of genotoxicity tests that included the bacterial        reverse mutation assay, in vitro mouse lymphoma point mutation        assay, chromosomal aberration studies in Chinese hamster ovarian        cells in vitro, and in vivo rat chromosomal aberration assay of        bone marrow cells.    -   Impairment of Fertility: Fertility studies have not been        conducted with Pennsaid Topical Solution. Diclofenac sodium        administered to male and female rats at doses up to 4 mg/kg/day        (1.4-fold of the MRHD of PENNSAID Topical Solution based on        apparent bioavailability and body surface area comparison) did        not affect fertility. Studies have not been conducted to        determine the safety of DMSO on fertility.

13.2 Animal Toxicology and/or Pharmacology

Ocular Effects

No adverse effects were observed using indirect ophthalmoscopy aftermultiple-daily dermal application to rats for 26 weeks and minipigs for52 weeks of DMSO at twice the concentration found in PENNSAID TopicalSolution. Published studies of dermal or oral administration of DMSO torabbits, dogs and pigs described refractive changes of lens curvatureand cortical fibers indicative of myopic changes and/or incidences oflens opacity or discoloration when evaluated using slit-lampbiomicroscopy examination, although no ocular abnormalities wereobserved in rhesus monkeys during daily oral or dermal treatment withDMSO for 9 to 18 months.

14. CLINICAL STUDIES

14.1 Pivotal Studies in Osteoarthritis of the Knee

The use of PENNSAID Topical Solution for the treatment of the signs andsymptoms of osteoarthritis of the knee was evaluated in two double-blindcontrolled trials conducted in the US and Canada, involving patientstreated with PENNSAID Topical Solution at a dose of 40 drops four timesa day for 12 weeks. PENNSAID Topical Solution was compared to topicalplacebo (2.3% DMSO with other excipients) and/or topical vehiclesolution (45.5% w/w DMSO with other excipients), applied directly to thestudy knee. In both trials, PENNSAID Topical

Solution treatment resulted in statistically significant clinicalimprovement compared to placebo and/or vehicle, in all three primaryefficacy variables—pain, physical function (Western Ontario and McMasterUniversities LK3.1 OA Index (WOMAC) pain and physical functiondimensions) and Patient Overall Health Assessment (POHA)/Patient GlobalAssessment (PGA). Numerical results are summarized in Tables 3 and 4.

TABLE 3 Change in treatment outcomes after 12 weeks of treatment in onestudy of efficacy of PENNSAID ® Topical Solution Study I Mean baselinescore and mean change in efficacy variables after 12 weeks of treatmentMean Topical Topical Baseline PENNSAID ® placebo¹ vehicle² EfficacyVariable score N = 154 N = 155 N = 161 WOMAC pain score 13 −6.0 −4.7−4.7 (Likert 3.1, 0-20) WOMAC physical 42 −15.7 −12.3 −12.1 function(Likert 3.1, 0-68) POHA (0-4) 2.3 −1.0 −0.4 −0.6 ¹placebo formulationincluded 2.3% DMSO ²vehicle formulation included 45.5% DMSO

TABLE 4 Change in treatment outcomes after 12 weeks of treatment in onestudy of efficacy of PENNSAID Topical Solution Study II Mean baselinescore and mean change in efficacy variables after 12 weeks of treatmentMean Topical Baseline PENNSAID vehicle¹ Efficacy Variable score N = 164N = 162 WOMAC pain score 13 −5.9 −4.4 (Likert 3.1, 0-20) WOMAC physical42 −15.3 −10.3 function (Likert 3.1, 0-68) PGA (0-4) 3.1 −1.3 −1.0¹vehicle formulation included 45.5% DMSO

16. HOW SUPPLIED/STORAGE AND HANDLING

PENNSAID Topical Solution is supplied as a clear, colorless to faintlypink-orange solution containing 16.05 mg of diclofenac sodium per mL ofsolution, in a white high density polyethylene bottle with a whitelow-density dropper cap.

16.1 NDC Number & Size

15 mL bottle (physician sample) NDC# 23635-310-11 60 mL bottle NDC #23635-310-60 150 mL bottle NDC # 23635-310-15

16.2 Storage

Store at 25° C. (77° F.); excursions permitted to 15-30° C. (59-86° F.)[See USP Controlled Room Temperature].

17. PATIENT COUNSELING INFORMATION

See Medication Guide.

17.1 Medication Guide

Inform patients of the following information before initiating therapywith an NSAID and periodically during the course of ongoing therapy.Encourage patients to read the NSAID Medication Guide that accompanieseach prescription dispensed prior to using PENNSAID Topical Solution.

17.2 Cardiovascular Effects

PENNSAID Topical Solution, like other NSAIDs, may cause serious CV sideeffects, such as MI or stroke, which may result in hospitalization andeven death. Although serious CV events can occur without warningsymptoms, instruct patients to be alert for the signs and symptoms ofchest pain, shortness of breath, weakness, slurring of speech, and toask for medical advice when observing any indicative sign or symptoms.Inform patients of the importance of this follow-up [see Warnings andPrecautions (5.1)].

17.3 Gastrointestinal Effects

PENNSAID Topical Solution, like other NSAIDs, may cause GI discomfortand, rarely, serious GI side effects, such as ulcers and bleeding, whichmay result in hospitalization and even death. Although serious GI tractulcerations and bleeding can occur without warning symptoms, informpatients to be alert for the signs and symptoms of ulceration andbleeding, and to ask for medical advice when observing any indicativesign or symptoms including epigastric pain, dyspepsia, melena, andhematemesis. Instruct patients of the importance of this follow-up [seeWarnings and Precautions (5.2)].

17.4 Hepatoxicity

Inform patients of the warning signs and symptoms of hepatotoxicity(e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upperquadrant tenderness, and “flu-like” symptoms). If these occur, instructpatients to stop therapy with PENNSAID Topical Solution and seekimmediate medical therapy [see Warnings and Precautions (5.3)].

17.5 Adverse Skin Reactions

PENNSAID Topical Solution, like other NSAIDs, can cause serious systemicskin side effects such as exfoliative dermatitis, SJS, and TEN, whichmay result in hospitalizations and even death. Although serious systemicskin reactions may occur without warning, instruct patients to be alertfor the signs and symptoms of skin rash and blisters, fever, or othersigns of hypersensitivity such as itching, and to ask for medical advicewhen observing any indicative signs or symptoms. [see Warnings andPrecautions (5.8)].

Advise patients to stop PENNSAID Topical Solution immediately if theydevelop any type of generalized rash and contact their physicians assoon as possible.

PENNSAID Topical Solution can cause a localized skin reaction at theapplication site. Advise patients to contact their physicians as soon aspossible if they develop any type of localized application site rash.

Instruct patients not to apply PENNSAID Topical Solution to open skinwounds, infections, inflammations, or exfoliative dermatitis, as it mayaffect absorption and reduce tolerability of the drug.

Instruct patients to wait until the area treated with Pennsaid topicalsolution is completely dry before applying sunscreen, insect repellant,lotion, moisturizer, cosmetics, or other topical medication.

Instruct patients to minimize or avoid exposure of treated knee(s) tonatural or artificial sunlight.

17.6 Weight Gain and Edema

Instruct patients to promptly report to their physician signs orsymptoms of unexplained weight gain or edema following treatment withPENNSAID Topical Solution [see Warnings and Precautions (5.5)].

17.7 Anaphylactoid Reactions

Inform patients of the signs of an anaphylactoid reaction (e.g.,difficulty breathing, swelling of the face or throat). If these occur,instruct patients to seek immediate emergency help [see Warnings andPrecautions (5.7)].

17.8 Effects During Pregnancy

Instruct patients who are pregnant or intending to become pregnant notto use Pennsaid Topical Solution. [see Use in Specific Populations (8.1)and Impairment of Fertility (13.1)]

17.9 Eye Exposure

Instruct patients to avoid contact of PENNSAID Topical Solution with theeyes and mucosa. Advise patients that if eye contact occurs, immediatelywash out the eye with water or saline and consult a physician ifirritation persists for more than an hour.

Revised—02/2009r Manufactured for: Mallinckrodt Brand Pharmaceuticals,Inc. Hazelwood, Mo. 63042 USA Manufactured By:

Nuvo Manufacturing (a division of Nuvo Research Inc.)

Varennes, Quebec, Canada J3X 1P7 Medication Guide For Non-steroidalAnti-Inflammatory Drugs (NSAIDS)

(See the end of this Medication Guide for a list of prescription NSAIDmedicines.)

What is the most important information I should know about medicinescalled Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

-   -   NSAID medicines may increase the chance of a heart attack or        stroke that can lead to death. This chance increases:        -   with longer use of NSAID medicines        -   in people who have heart disease    -   NSAID medicines should never be used right before or after a        heart surgery called a “coronary artery bypass graft (CABG).”    -   NSAID medicines can cause ulcers and bleeding in the stomach and        intestines at any time during treatment. Ulcers and bleeding:        -   can happen without warning symptoms        -   may cause death    -   The chance of a person getting an ulcer or bleeding increases        with:        -   taking medicines called “corticosteroids” and            “anticoagulants”        -   longer use        -   smoking        -   drinking alcohol        -   older age        -   having poor health    -   NSAID medicines should only be used:        -   exactly as prescribed        -   at the lowest dose possible for your treatment        -   for the shortest time needed    -   What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?    -   NSAID medicines are used to treat pain and redness, swelling,        and heat (inflammation) from medical conditions such as:        -   different types of arthritis        -   menstrual cramps and other types of short-term pain    -   Who should not take a Non-Steroidal Anti-Inflammatory Drug        (NSAID)? Do not take an NSAID medicine:        -   if you had an asthma attack, hives, or other allergic            reaction with aspirin or any other NSAID medicine        -   for pain right before or after heart bypass surgery    -   Tell your healthcare provider:        -   about all of your medical conditions.        -   about all of the medicines you take. NSAIDs and some other            medicines can interact with each other and cause serious            side effects. Keep a list of your medicines to show to your            healthcare provider and pharmacist.        -   if you are pregnant. NSAID medicines should not be used by            pregnant women late in their pregnancy.        -   if you are breastfeeding. Talk to your doctor.            What are the possible side effects of Non-Steroidal            Anti-Inflammatory Drugs (NSAIDs)?

Other side Serious side effects include: effects include: heart attackstomach pain stroke constipation high blood pressure diarrhea heartfailure from body swelling (fluid retention) gas kidney problemsincluding kidney failure heartburn bleeding and ulcers in the stomachand intestine nausea low red blood cells (anemia) vomitinglife-threatening skin reactions dizziness life-threatening allergicreactions liver problems including liver failure asthma attacks inpeople who have asthmaGet emergency help right away if you have any of the following symptoms:

shortness of breath or trouble breathing slurred speech chest painswelling of the face or throat weakness in one part or side of your bodyStop your NSAID medicine and call your healthcare provider right away ifyou have any of the following symptoms:

nausea there is blood in your bowel more tired or weaker than usualmovement or it is black and itching sticky like tar your skin or eyeslook yellow unusual weight gain stomach pain skin rash or blisters withfever flu-like symptoms swelling of the arms and legs, vomit blood handsand feetThese are not all the side effects with NSAID medicines. Talk to yourhealthcare provider or pharmacist for more information about NSAIDmedicines.Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs):

Aspirin is an NSAID medicine but it does not increase the chance of aheart attack. Aspirin can cause bleeding in the brain, stomach, andintestines. Aspirin can also cause ulcers in the stomach and intestines.

Some of these NSAID medicines are sold in lower doses without aprescription (over-the-counter). Talk to your healthcare provider beforeusing over-the-counter NSAIDs for more than 10 days.

NSAID medicines that need a prescription

Generic Name Tradename Celecoxib Celebrex Diclofenac Flector, Cataflam,Voltaren, Arthrotec ™ (combined with misoprostol), PENNSAID TopicalSolution Diflunisal Dolobid Etodolac Lodine, LodineXL Fenoprofen Nalfon,Nalfon200 Flurbirofen Ansaid Ibuprofen Motrin, Tab-Profen, Vicoprofen*(combined with hydro- codone), Combunox ™ (combined with oxycodone)Indomethacin Indocin, IndocinSR, Indo-Lemmon ™, Indomethagan ™Ketoprofen Oruvail Ketorolac Toradol Mefenamic Ponstel Acid MeloxicamMobic Nabumetone Relafen Naproxen Naprosyn, Anaprox, AnaproxDS,EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole) OxaprozinDaypro Piroxicam Feldene Sulindac Clinoril Tolmetin Tolectin, TolectinDS, Tolectin600 *Vicoprofen contains the same dose of ibuprofen asover-the-counter (OTC) NSAID, and is usually used for less than 10 daysto treat pain. The OTC NSAID label warns that long term continuous usemay increase the risk of heart attack or stroke.This Medication Guide has been approved by the U.S. Food and DrugAdministration.

Revised: Month Year Patient Instructions for Use PENNSAID [pen/sed]Diclofenac Sodium Topical Solution

Your doctor has prescribed PENNSAID® Topical Solution to treat your painfrom osteoarthritis in your knee(s) and help you manage your dailyactivities better.

Before you use PENNSAID® Topical Solution:

-   -   Apply PENNSAID® Topical Solution exactly as your doctor tells        you. Do not apply PENNSAID® Topical Solution anywhere on your        body other than where your doctor tells you.    -   Apply PENNSAID® Topical Solution on clean, dry skin that does        not have any cuts, infections or rashes.    -   Use PENNSAID® Topical Solution 4 times each day on your knee(s).    -   Do not get PENNSAID® Topical Solution in your eyes, nose or        mouth. Only use PENNSAID® Topical Solution on your skin (topical        use). If you get PENNSAID® Topical Solution in your eyes, rinse        your eyes right away with water or saline. Call your doctor if        your eyes are irritated for more than one hour.        Steps for using PENNSAID® Topical Solution:

-   Step 1. Wash your hands with soap and water before and after    applying PENNSAID® Topical Solution.

-   Step 2. Your total dose for each knee is 40 drops of PENNSAID®    Topical Solution. You will use 10 drops at a time. Put 10 drops of    PENNSAID® Topical Solution either on your hand or directly on your    knee.    -   See FIG. 10A.

-   Figure 1. Dispense 10 drops of PENNSAID® at a time

-   Step 3. Spread PENNSAID® Topical Solution evenly on the front, back    and sides of your knee. Repeat this step 4 times so that your knee    is completely covered with a total of 40 drops of PENNSAID® Topical    Solution.    -   See FIGS. 10B & 10C.

-   Figure 2. Spread PENNSAID® evenly on the front, and sides of your    knee

-   Figure 3. Spread PENNSAID® evenly on the back of your knee

-   Step 4. Repeat steps 2 and 3 for the other knee if needed.

After you use PENNSAID® Topical Solution: Do not

-   -   cover your knee with clothing until your knee is completely dry    -   put sunscreen, insect repellant, lotion, moisturizer, cosmetics,        or other topical medicines on your knee until it is completely        dry    -   take a shower or a bath for at least 30 minutes after you put        PENNSAID® Topical Solution on your knee(s).    -   use heating pads or apply bandages to the skin where you have        applied PENNSAID® Topical Solution.    -   expose your skin to sunlight or artificial light (tanning        booths) where you have put PENNSAID® Topical Solution.        How should I store PENNSAID® Topical Solution?:    -   Store PENNSAID® Topical Solution between 59° F. to 86° F.        (15° C. to 30° C.).

Keep PENNSAID® Topical Solution and all medicines out of the reach ofchildren.

All patents, publications, scientific articles, web sites, and otherdocuments and materials referenced or mentioned herein are indicative ofthe levels of skill of those skilled in the art to which the inventionpertains, and each such referenced document and material is herebyincorporated by reference to the same extent as if it had beenincorporated by reference in its entirety individually or set forthherein in its entirety. Applicants reserve the right to physicallyincorporate into this specification any and all materials andinformation from any such patents, publications, scientific articles,web sites, electronically available information, and other referencedmaterials or documents.

The written description portion of this patent includes all claims.Furthermore, all claims, including all original claims as well as allclaims from any and all priority documents, are hereby incorporated byreference in their entirety into the written description portion of thespecification, and Applicants reserve the right to physicallyincorporate into the written description or any other portion of theapplication, any and all such claims. Thus, for example, under nocircumstances may the patent be interpreted as allegedly not providing awritten description for a claim on the assertion that the precisewording of the claim is not set forth in haec verba in writtendescription portion of the patent.

The claims will be interpreted according to law. However, andnotwithstanding the alleged or perceived ease or difficulty ofinterpreting any claim or portion thereof, under no circumstances mayany adjustment or amendment of a claim or any portion thereof duringprosecution of the application or applications leading to this patent beinterpreted as having forfeited any right to any and all equivalentsthereof that do not form a part of the prior art.

All of the features disclosed in this specification may be combined inany combination. Thus, unless expressly stated otherwise, each featuredisclosed is only an example of a generic series of equivalent orsimilar features.

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Thus,from the foregoing, it will be appreciated that, although specificnonlimiting embodiments of the invention have been described herein forthe purpose of illustration, various modifications may be made withoutdeviating from the spirit and scope of the invention. Other aspects,advantages, and modifications are within the scope of the followingclaims and the present invention is not limited except as by theappended claims.

The specific methods and compositions described herein arerepresentative of preferred nonlimiting embodiments and are exemplaryand not intended as limitations on the scope of the invention. Otherobjects, aspects, and embodiments will occur to those skilled in the artupon consideration of this specification, and are encompassed within thespirit of the invention as defined by the scope of the claims. It willbe readily apparent to one skilled in the art that varying substitutionsand modifications may be made to the invention disclosed herein withoutdeparting from the scope and spirit of the invention. The inventionillustratively described herein suitably may be practiced in the absenceof any element or elements, or limitation or limitations, which is notspecifically disclosed herein as essential. Thus, for example, in eachinstance herein, in nonlimiting embodiments or examples of the presentinvention, the terms “comprising”, “including”, “containing”, etc. areto be read expansively and without limitation. The methods and processesillustratively described herein suitably may be practiced in differingorders of steps, and that they are not necessarily restricted to theorders of steps indicated herein or in the claims.

The terms and expressions that have been employed are used as terms ofdescription and not of limitation, and there is no intent in the use ofsuch terms and expressions to exclude any equivalent of the featuresshown and described or portions thereof, but it is recognized thatvarious modifications are possible within the scope of the invention asclaimed. Thus, it will be understood that although the present inventionhas been specifically disclosed by various nonlimiting embodimentsand/or preferred nonlimiting embodiments and optional features, any andall modifications and variations of the concepts herein disclosed thatmay be resorted to by those skilled in the art are considered to bewithin the scope of this invention as defined by the appended claims.

The invention has been described broadly and generically herein. Each ofthe narrower species and subgeneric groupings falling within the genericdisclosure also form part of the invention. This includes the genericdescription of the invention with a proviso or negative limitationremoving any subject matter from the genus, regardless of whether or notthe excised material is specifically recited herein.

It is also to be understood that as used herein and in the appendedclaims, the singular forms “a,” “an,” and “the” include plural referenceunless the context clearly dictates otherwise, the term “X and/or Y”means “X” or “Y” or both “X” and “Y”, and the letter “s” following anoun designates both the plural and singular forms of that noun. Inaddition, where features or aspects of the invention are described interms of Markush groups, it is intended, and those skilled in the artwill recognize, that the invention embraces and is also therebydescribed in terms of any individual member and any subgroup of membersof the Markush group, and applicants reserve the right to revise theapplication or claims to refer specifically to any individual member orany subgroup of members of the Markush group.

Other nonlimiting embodiments are within the following claims. Thepatent may not be interpreted to be limited to the specific examples ornonlimiting embodiments or methods specifically and/or expresslydisclosed herein. Under no circumstances may the patent be interpretedto be limited by any statement made by any Examiner or any otherofficial or employee of the Patent and Trademark Office unless suchstatement is specifically and without qualification or reservationexpressly adopted in a responsive writing by Applicants.

1.-20. (canceled)
 21. A method for treating pain in a patient followingan invasive medical procedure or surgery, said method comprising:applying a medication consisting of a topical diclofenac preparation toa site of pain and/or to a skin location proximal thereto of saidpatient, wherein the topical diclofenac preparation consists of 2% w/wof a salt of diclofenac; about 40% to about 50% w/w dimethyl sulfoxide;about 23-29% w/w ethanol; about 10-12% w/w propylene glycol; about 0-6%w/w hydroxypropylcellulose; and water to make 100% w/w; wherein thetopical diclofenac preparation has a viscosity of 500-5000 centipoise,and wherein said medication is applied twice daily.
 22. The methodaccording to claim 21, wherein said salt of diclofenac is selected froma sodium salt, a potassium salt, a diethylamine salt, and an epolaminesalt.
 23. The method according to claim 21, wherein said salt ofdiclofenac is diclofenac sodium.
 23. The method according to claim 21,wherein said dimethyl sulfoxide is present at 45.5% w/w.
 24. A methodfor treating pain in a supporting body structure of a patient, saidmethod comprising: applying a medication consisting of a topicaldiclofenac preparation to a site of pain of said patient, wherein thetopical diclofenac preparation consists of 2% w/w of a salt ofdiclofenac; about 40% to about 50% w/w dimethyl sulfoxide; about 23-29%w/w ethanol; about 10-12% w/w propylene glycol; about 0-6% w/whydroxypropylcellulose; and water to make 100% w/w; wherein the topicaldiclofenac preparation has a viscosity of 500-5000 centipoise, whereinsaid medication is applied twice daily, and wherein the supporting bodystructure is selected from muscles, bones, tendons, ligaments andcartilage.
 25. The method according to claim 24, wherein said dimethylsulfoxide is present at 45.5% w/w.
 26. The method according to claim 24,wherein said salt of diclofenac is selected from a sodium salt, apotassium salt, a diethylamine salt, and an epolamine salt.
 27. Themethod according to claim 24, wherein said salt of diclofenac isdiclofenac sodium.